| 1. |
- Wan, Y., et al.
(författare)
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First reported nonpeptide AT1 receptor agonist (L-162,313) acts as an AT2 receptor agonist in vivo
- 2004
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Ingår i: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:6, s. 1536-1546
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Tidskriftsartikel (refereegranskat)abstract
- In this investigation, it is demonstrated that the first nonpeptide AT(1) receptor agonist L-162,313 (1), disclosed in 1994, also acts as an agonist at the AT(2) receptor. In anesthetized rats, administration of compound 1 intravenously or locally in the duodenum increased duodenal mucosal alkaline secretion, effects that were sensitive to the selective AT(2) receptor antagonist PD-123,319. The data strongly suggest that 1 is an AT(2) receptor agonist in vivo. To the best of our knowledge, this substance is the first nonpeptidic low-molecular weight compound with an agonistic effect mediated through the AT(2) receptor.
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| 2. |
- Andersson, Hanna, 1979-, et al.
(författare)
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Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
- 2011
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51, s. 3779-3792
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Tidskriftsartikel (refereegranskat)abstract
- Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.
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| 3. |
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| 4. |
- Andersson, Hanna, 1979-
(författare)
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Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.
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| 5. |
- Andersson, Hanna, 1979-, et al.
(författare)
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Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:22, s. 8059-8071
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.
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| 6. |
- Ax, Anna, 1975-
(författare)
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Cyclic Sulfamide HIV-1 Protease Inhibitors : Design, Synthesis and Modelling
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ten years ago, the first protease inhibitor targeting the human immunodeficiency virus (HIV) was approved for clinical use. Highly active antiretroviral therapy (HAART), which combined protease and reverse transcriptase inhibitors, quickly became the standard therapy for treating patients infected with HIV and Acquired Immune Deficiency Syndrome (AIDS). Nevertheless, last year the AIDS pandemic reached its highest level ever. Many infected patients, mainly in the developing countries, are still without treatment. Among those patients who receive treatment, an increase in drug resistance and new-infection with drug-resistant strains are seen. To come to terms with these problems, new drugs that are efficient against resistant strains and can be produced at low cost are needed.In this study, we have focused our research efforts on cyclic sulfamides active as HIV-1 protease inhibitors. Distinctive to this compound class, as compared to the inhibitors so far approved for clinical use, was the incorporation of a water mimic that displaces the structural water (W301) observed in the X-ray crystal co-complexes. The first part of the study was aimed at understanding the rationale behind the nonsymmetric binding mode that the inhibitor adopted when bound to the enzyme. Symmetric and nonsymmetric inhibitors were synthesized and the structure-activity relationships and preferable binding modes were rationalized with the help of Comparative Molecular Field Analysis (CoMFA).In the second part of the study, an attempt was made to reduce the size of these inhibitors. As a result, the traditional P1/P1' substituents were removed, while the P2/P2' substituents were elongated in an attempt to reach between the binding sites. The design hypothesis was shown to be successful and inhibitors possessing nanomolar activity were identified.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Ax, Anna, et al.
(författare)
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Synthesis of a small library of non-symmetric cyclic sulfamide HIV-1 protease inhibitors
- 2010
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 66:23, s. 4049-4056
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Tidskriftsartikel (refereegranskat)abstract
- A set of 11 non-symmetric cyclic sulfamide HIV-1 protease inhibitors were synthesized and evaluated. The use of a key microwave-assisted silver(I) oxide mediated selective mono N-benzylation reaction enabled fast and straightforward synthesis. The K-i values of the new inhibitors ranged between 0.28 mu M and >20 mu M.
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| 11. |
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| 12. |
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| 13. |
- Bäckbro, Kristina, et al.
(författare)
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Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 898-902
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Tidskriftsartikel (refereegranskat)abstract
- Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 Å resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
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| 14. |
- Garg, Neeraj, et al.
(författare)
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Preparation of cis-5-methoxy-and-7-methoxy-1-acetoxy-1,2,3,4,4a,10a-hexahydro-9(10H)-phenanthrenone. An epoxide-arene reaction involving a selective 1,2-alkyl shift rearrangement
- 1996
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Ingår i: Tetrahedron. - 0040-4020 .- 1464-5416. ; 52:48, s. 15209-15224
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Tidskriftsartikel (refereegranskat)abstract
- The preparation of cis-1α-acetoxy-7-methoxy-1,2,3,4,4a,10a-hexahydro-9(10H)- phenanthrenone 5 was accomplished starting from 6-methoxy-1-tetralone. Reduction of 7-methoxy-1,2,3, 4,9,10-hexahydro-1-oxo-phenanthrene 8, acetylation and subsequent oxidation delivered 5. Application of an analogus procedure to the preparation of cis-1β-acetoxy-5-methoxy-1,2,3,4,,4a,10a-hexahydro-9(10H)- phenanthrenone 6 was not feasible. A more elaborate route was developed for the synthesis of compound 6, where an epoxide-arene reaction involving a 1,2-alkyl shift rearrangement, constituted a highly selective key transformation. The compounds 5 and 6 were prepared. A route was developed for the synthesis of compound 6, where an epoxide-arene reaction involving a 1,2-alkyl shift rearrangement, constituted a highly selective key transformation.
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| 15. |
- Georgsson, Jennie, et al.
(författare)
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Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:21, s. 6620-6631
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Tidskriftsartikel (refereegranskat)abstract
- Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as γ-turn mimics.
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| 16. |
- Georgsson, Jennie, et al.
(författare)
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Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5963-5972
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Tidskriftsartikel (refereegranskat)abstract
- Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.
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| 17. |
- Georgsson, Jennie, et al.
(författare)
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Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:7, s. 1711-1715
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Tidskriftsartikel (refereegranskat)abstract
- Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Hultén, Johan, et al.
(författare)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Tidskriftsartikel (refereegranskat)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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| 23. |
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| 24. |
- Hämäläinen, Markku D., et al.
(författare)
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Characterization of a set of HIV-1 protease inhibitors using binding kinetics data from a biosensor-based screen
- 2000
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 5:5, s. 353-359
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Tidskriftsartikel (refereegranskat)abstract
- The interaction between 290 structurally diverse human immunodeficiency virus type 1 (HIV-1) protease inhibitors and the immobilized enzyme was analyzed with an optical biosensor, Although only a single concentration of inhibitor was used, information about the kinetics of the interaction could be obtained by extracting binding signals at discrete time points. The statistical correlation between the biosensor binding data, inhibition of enzyme activity (K-i), and viral replication (EC50) revealed that the association and dissociation rates for the interaction could be resolved and that they were characteristic for the compounds. The most potent inhibitors, with respect to K-i and EC50 values, including the clinically used drugs, all exhibited fast association and slow dissociation rates. Selective or partially selective binders for HIV-1 protease could be distinguished from compounds that showed a general protein-binding tendency by using three reference target proteins. This biosensor-based direct binding assay revealed a capacity to efficiently provide high-resolution information on the interaction kinetics and specificity of the interaction of a set of compounds with several targets simultaneously.
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| 25. |
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| 26. |
- Johannesson, Petra, et al.
(författare)
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Angiotensin II analogues encompassing 5,9-and 5,10-fused thiabicycloalkane tripeptide mimetics
- 1999
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 42:22, s. 4524-4537
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Tidskriftsartikel (refereegranskat)abstract
- A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precurso
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| 27. |
- Johannesson, Petra, et al.
(författare)
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Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor
- 2002
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 45:9, s. 1767-1777
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Tidskriftsartikel (refereegranskat)abstract
- Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.
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| 28. |
- Lagerlund, Olof
(författare)
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Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed. A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS. A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized. The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.
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| 29. |
- Lindman, Susanna, et al.
(författare)
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Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II
- 2001
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 9:3, s. 763-772
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Tidskriftsartikel (refereegranskat)abstract
- Cyclic 12-, 13- and 14-membered ring angiotensin II analogues related to disulfides but encompassing methylenedithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the disulfides. The methylenedithioether analogues displayed good binding affinities to rat liver AT1 receptors although in most cases somewhat lower than their disulfide counterparts. One of the methylenedithioethers with a 13-membered ring system demonstrated the highest binding affinity among the thioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and the corresponding methylenedithioether analogues and also between the ring size homologues. This analysis also suggested that some of the model compounds were prone to adopt inverse γ-turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in the series. The easily executed methylenedithioether cyclization should constitute a valuable complement to the common disulfide methodology for fine-tuning and for probing the bioactive conformation of peptides.
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| 30. |
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| 31. |
- Muthas, Daniel, 1976-
(författare)
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Development and Application of Computational Methods in Antitubercular Drug Design : Identification of Novel Inhibitors of Ribonucleotide Reductase
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis kills approximately 1.7 million people each year around the world making it one of the most lethal infectious diseases. This thesis concerns the development of two computational tools that can support the early stages of drug discovery, and their use in an anti-tubercular drug discovery program. One of the tools developed is a statistical molecular design (SMD) approach that generates information-rich libraries biased towards a lead structure. The other metod is a post-filtering technique to increase the success of virtual screening, has also been developed. Both methods have been validated using literature data. Ribonucleotide reductase (RNR) has been identified as a potential anti-tubercular target, and our focus has been to develop small-molecule inhibitors of this target. The enzyme consists of two subunits (a large R1 and a small R2 subunit) that have to associate in order to generate a bioactive complex. It had previously been shown that a heptapeptide corresponding to the small R2 subunits C-terminal inhibited the enzyme. In order to investigate the requirements for inhibitory effect of the peptide a library was designed using the developed SMD approach. The designed library was synthesized and evaluated for biological activity and an OPLS-DA model was derived to understand which positions were most important for activity. In order to identify small-molecule inhibitors of RNR a combined shape- and structure-based virtual screen was performed, employing ROCS, GlideXP and the developed post-filtering technique. Starting from a library of 1.5 million compounds 24 was acquired and evaluated for enzymatic activity. The best compounds were almost as potent as the starting peptide, but considerably more drug-like.
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| 32. |
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| 33. |
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| 34. |
- Nordqvist, Anneli, 1978-
(författare)
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Hit Identification and Hit Expansion in Antituberculosis Drug Discovery : Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the discovery of Mycobacterium tuberculosis (Mtb) as the bacterial agent causing tuberculosis, the permanent eradication of this disease has proven challenging. Although a number of drugs exist for the treatment of tuberculosis, 1.7 million people still die every year from this infection. The current treatment regimen involves lengthy combination therapy with four different drugs in an effort to combat the development of resistance. However, multidrug-resistant and extensively drug-resistant strains are emerging in all parts of the world. Therefore, new drugs effective in the treatment of tuberculosis are much-needed. The work presented in this thesis was focused on the early stages of drug discovery by applying different hit identification and hit expansion strategies in the exploration of two new potential drug targets, glutamine synthetase (GS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). A literature survey was first carried out to identify new Mtb GS inhibitors from compounds known to inhibit GS in other species. Three compounds, structurally unrelated to the typical amino acid derivatives of previously known GS inhibitors, were then discovered by virtual screening and found to be Mtb GS inhibitors, exhibiting activities in the millimolar range. Imidazo[1,2-a]pyridine analogues were also investigated as Mtb GS inhibitors. The chemical functionality, size requirements and position of the substituents in the imidazo[1,2-a]pyridine hit were investigated, and a chemical library was designed based on a focused hierarchical design of experiments approach. The X-ray structure of one of the inhibitors in complex with Mtb GS provided additional insight into the structure–activity relationships of this class of compounds. Finally, new α-arylated fosmidomycin analogues were synthesized as inhibitors of Mtb DXR, exhibiting IC50 values down to 0.8 µM. This work shows that a wide variety of aryl groups are tolerated by the enzyme. Cinnamaldehydes are important synthetic intermediates in the synthesis of fosmidomycin analogues. These were prepared by an oxidative Heck reaction from acrolein and various arylboronic acids. Electron-rich, electron-poor, heterocyclic and sterically hindered boronic acids could be employed, furnishing cinnamaldehydes in 43–92% yield.
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| 35. |
- Nurbo, Johanna, 1979-
(författare)
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Peptidomimetic Enzyme Inhibitors : Targeting M. tuberculosis Ribonucleotide Reductase and Hepatitis C Virus NS3 Protease
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the design and synthesis of inhibitors targeting Mycobacterium tuberculosis ribonucleotide reductase (RNR) and hepatitis C virus (HCV) NS3 protease; enzymes that have been identified as potential drug targets for the treatment of tuberculosis and hepatitis C, respectively. Small peptides have been recognized as inhibitors of these enzymes. However, the use of peptides as drugs is limited due to their unfavorable properties. These can be circumvented by the development of less peptidic molecules, often referred to as peptidomimetics. When this work was initiated, only a few inhibitors targeting M. tuberculosis RNR had been identified, whereas the HCV NS3 protease was an established drug target. Therefore, early peptidomimetic design strategies were applied to inhibitors of RNR while the NS3 protease inhibitors were subjected to modifications in a later stage of development. It has previously been shown that peptides derived from the C-terminus of the small subunit of M. tuberculosis RNR can compete for binding to the large subunit, and thus inhibit enzyme activity. To investigate the structural requirements of these inhibitors, different series of peptides were evaluated. First, peptides from an N-terminal truncation, an alanine scan and a designed library were synthesized and evaluated to examine the importance of the individual amino acid residues. Then, a set of N-terminally Fmoc-protected peptides was evaluated, and it was found that the N-terminal group improved the affinity of the peptides even when the length of the compounds was reduced. Furthermore, potential inhibitors of less peptidic character were generated by the introduction of a benzodiazepine-based scaffold. To further reduce the peptidic character and investigate the binding properties of HCV NS3 protease inhibitors, a series of tripeptides incorporating a β-amino acid was synthesized. Inhibition was evaluated and docking studies were performed to understand how the structural changes affected inhibitory potency. The results illustrated the importance of preserving the hydrogen bonding network and retaining electrostatic interactions in the oxyanion hole between inhibitor and protein.
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| 36. |
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| 37. |
- Rosenström, Ulrika, et al.
(författare)
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A Selective AT2 Receptor Ligand with a γ-Turn-Like Mimetic replacing the Amino Acid Residues 4-5 of Angiotensin II
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:4, s. 859-870
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Tidskriftsartikel (refereegranskat)abstract
- Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based γ-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT1 receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT2 receptor (Ki = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT2 receptor was that the guanidino group of the Arg2 residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S−CH2−S)[Cys3,5]Ang II which is known to bind with high affinity to the AT2 receptor (Ki = 0.62 nM). This comparison showed that, in the compounds with high AT2 receptor affinity, the guanidino group of the Arg2 residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg2 for Ala2 in the analogue having the high affinity. This analogue lacked affinity to AT2 receptors, which supports the role of the guanidino group in receptor binding.
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| 38. |
- Rosenström, Ulrika, et al.
(författare)
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Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:20, s. 6133-6137
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Tidskriftsartikel (refereegranskat)abstract
- A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT(2) receptor, and one also displayed high affinity for the AT(1) receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT(2) receptor ligands.
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| 39. |
- Rosenström, Ulrika, et al.
(författare)
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New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:12, s. 4009-4024
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Tidskriftsartikel (refereegranskat)abstract
- New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.
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| 40. |
- Rosenström, Ulrika, et al.
(författare)
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Synthesis and AT2 receptor-binding properties of angiotensin II analogues
- 2004
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Ingår i: Journal of Peptide Research. - : Wiley. - 1397-002X .- 1399-3011. ; 64:5, s. 194-201
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2–8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 μm). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.
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| 41. |
- Russo, Francesco, et al.
(författare)
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Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
- 2015
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 4:3, s. 342-362
-
Tidskriftsartikel (refereegranskat)abstract
- This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
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| 42. |
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| 43. |
- Schmidt, Boris, et al.
(författare)
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Design, synthesis, and biological activities of four angiotensin IIreceptor ligands with gamma-turn mimetics replacing amino acid residues 3-5
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40, s. 903-919
-
Tidskriftsartikel (refereegranskat)abstract
- Disulfide cyclization is a powerful method for reducing the conformational space of a peptide. This in turn may enable the study of its bioactive conformation. Several analogues of angiotensin II (Ang II) containing a disulfide bridge between amino acids 3 and 5 have been reported. Among these the cyclic octapeptides c[Hcy3,5]-Ang II, c[Cys3,5]-Ang II, and c[Pen 3,5]-Ang II showed significant activity at Ang II receptors. We have performed conformational analysis studies using theoretical calculations and 1H-NMR spectroscopy on tripeptide model compounds of these cyclic octapeptides which show that the cyclic moieties of c[Cys3,5]-Ang II and c[Pen3,5]-Ang II preferentially assume an inverse gamma-turn conformation. On the basis of these results, we substituted amino acid residues 3-5 in Ang II with two different gamma-turn mimetics giving four diastereomeric Ang II analogues. Interestingly, two of these are equipotent to Ang II in binding to AT1 receptors. In the contractile test using rabbit aorta rings, one of the analogues is an agonist with full contractile activity approximately equipotent to c[Pen3,5]-Ang II but 300-fold less potent than Ang II. This low potency may suggest that Ang II does not adopt a gamma-turn in the 3-5 region when interacting with the receptor.
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| 44. |
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| 45. |
- Sjöberg, Mats, 1965-, et al.
(författare)
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Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis : a retrospective observational study
- 2012
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Ingår i: Inflammatory Bowel Diseases. - : John Wiley & Sons. - 1078-0998 .- 1536-4844. ; 18:2, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives. Methods: Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n 49) treated with a single infusion of IFX; 2) an Austrian cohort (n 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy. Results: At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality. Conclusions: Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.
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| 46. |
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| 47. |
- Sköld, Christian, 1976-
(författare)
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Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands : Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor. The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan. To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor. By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived.
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| 48. |
- Wallinder, Charlotta, 1976-
(författare)
-
Design, Synthesis and Biological Evaluation of Selective Nonpeptide AT2 Receptor Agonists and Antagonists
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The G protein-coupled receptors (GPCRs) are important targets in drug discovery. In several cases, the endogenous ligands that activate the GPCRs of pharmaceutical interest are peptides. Unfortunately, peptides are in general not suitable as drugs, since the peptide structure is associated with several disadvantages, such as low oral bioavailability, rapid degradation and low receptor subtype selectivity. Thus, there is a strong need for drug-like nonpeptide ligands to peptide-activated GPCRs. However, to discover nonpeptide ligands that mimic the effect of the endogenous peptide, i.e. peptidomimetics, is a tremendous challenge. In fact, morphine and the related opioids were the only known examples of peptidomimetics before 1995 and these ligands were known long before the native endogenous peptide ligands were discovered. The main objective of the work described in this thesis was to design, synthesize and biologically evaluate selective nonpeptide agonists to the peptide-activated GPCR AT2. The AT2 receptor belongs to the renin–angiotensin system, where the octapeptide angiotensin II (Ang II) is the major effector peptide. Ang II mediates its effects through the two GPCRs AT1 and AT2. The AT1 receptor is already an established target in the treatment of hypertension. The physiological role of the AT2 receptor, which is up-regulated in certain pathological conditions, is not fully understood but it seems to include positive effects such as vasodilatation, tissue repair, tissue regeneration and neuronal differentiation. In the current investigation we started from the nonpeptide and nonselective (AT1/ AT2) compound L-162,313. This ligand is a known AT1 receptor agonist but its effect on the AT2 receptor was unknown at the start of this project. We were able to show that it acts as an agonist also at the AT2 receptor. Furthermore, stepwise synthetic modifications of L-162,313 led to the identification of the first selective nonpeptide AT2 receptor agonist. Following the discovery of this compound several selective nonpeptide AT2 receptor agonists were identified. It was also revealed that a minor structural alteration of one of these compounds interconverted the functional activity from agonism to antagonism. The structural requirement for agonism vs antagonism was therefore studied. The functionality switch was suggested, at least partly, to be due to the spatial relationship between the methyleneimidazole group and the isobutyl side chain of the compounds. To further investigate the bioactive conformation(s) of this series of compounds enantiomerically pure analogues with conformationally constrained isobutyl chains were prepared. This study revealed that the direction of the isobutyl side chain determine whether the compounds act as agonists or antagonists at the AT2 receptor. Further investigations are required to fully elucidate the bioactive conformation(s) of these nonpeptide AT2 receptor agonists.We believe that the selective nonpeptide AT2 receptor agonists and antagonists identified in this thesis will serve as important research tools in the continuing investigation of the physiological role of the AT2 receptor. We also believe that these drug-like compounds might provide potential leads in drug discovery processes.
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| 49. |
- Wannberg, Johan, et al.
(författare)
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A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 14:15, s. 5303-5315
-
Tidskriftsartikel (refereegranskat)abstract
- In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.
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| 50. |
- Zuccarello, Guido, et al.
(författare)
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HIV-1 protease inhibitors based on acyclic carbohydrates
- 1998
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:15, s. 4898-4906
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Tidskriftsartikel (refereegranskat)abstract
- A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.
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