| 1. |
- Dahlgren, Anders, et al.
(författare)
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Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors : design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:6, s. 1829-1839
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Tidskriftsartikel (refereegranskat)abstract
- A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.
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| 2. |
- Nilsson, Jonas W., et al.
(författare)
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Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
- 2001
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Ingår i: Journal of Combinatorial Chemistry. - : American Chemical Society (ACS). - 2156-8952 .- 1520-4766 .- 1520-4774. ; 3:6, s. 546-553
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Tidskriftsartikel (refereegranskat)abstract
- Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.
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| 3. |
- Nilsson, Jonas W., et al.
(författare)
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Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold : Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
- 2001
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:19, s. 3985-4001
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Tidskriftsartikel (refereegranskat)abstract
- A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in d-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of α-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 μM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with α-thrombin is discussed.
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| 4. |
- Thorstensson, Fredrik, et al.
(författare)
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Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
- 2003
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:7, s. 1165-1179
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Tidskriftsartikel (refereegranskat)abstract
- The thrombin inhibitory tripeptide d-Phe-Pro-Arg has been mimicked using either cyclopentenedicarboxylic derivatives or a cyclohexenedicarboxylic derivative as surrogate for the P2 proline. In the P3 position, tertiary amides were optimized as d-Phe P3 replacements. The P1 arginine was, in all compounds, substituted with the more rigid and biocompatible 4-aminomethylbenzamidine. One of the novel inhibitors was cocrystallized with α-thrombin and subjected to X-ray analysis. From analysis of the X-ray crystal structure, new ligands were designed leading to significantly improved binding affinity, the lead candidate exhibiting an in vitro IC50 of 49 nM.
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| 5. |
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| 6. |
- Andersson, H.O., et al.
(författare)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
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| 7. |
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| 8. |
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| 9. |
- Bäck, Marcus, 1979-
(författare)
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Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-1
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.
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| 10. |
- Bäck, Marcus, et al.
(författare)
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Design, synthesis and SAR of potent statine-based BACE-1 inhibitors : Exploration of P1 phenoxy and benzyloxy residues
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:21, s. 9471-9486
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Tidskriftsartikel (refereegranskat)abstract
- Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modi. cation introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.
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| 11. |
- Bäck, Marcus, et al.
(författare)
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Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease : use of cyclopentane and cyclopentene P2-motifs
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7184-7202
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Tidskriftsartikel (refereegranskat)abstract
- Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
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| 12. |
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| 13. |
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| 14. |
- Dahlgren, Anders, et al.
(författare)
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New inhibitors of the malaria aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:16, s. 3423-3437
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Tidskriftsartikel (refereegranskat)abstract
- New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.
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| 15. |
- Dahlgren, Anders, et al.
(författare)
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Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:6, s. 827-841
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.
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| 16. |
- Dahlgren, Anders, et al.
(författare)
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Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:5, s. 1567-1580
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Tidskriftsartikel (refereegranskat)abstract
- With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC50~5.9 µM. © 2002 Elsevier Science Ltd. All rights reserved.
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| 17. |
- Hagström, Åsa, 1975-
(författare)
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Understanding Certificate Revocation
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Correct certificate revocation practices are essential to each public-key infrastructure. While there exist a number of protocols to achieve revocation in PKI systems, there has been very little work on the theory behind it: Which different types of revocation can be identified? What is the intended effect of a specific revocation type to the knowledge base of each entity?As a first step towards a methodology for the development of reliable models, we present a graph-based formalism for specification and reasoning about the distribution and revocation of public keys and certificates. The model is an abstract generalization of existing PKIs and distributed in nature; each entity can issue certificates for public keys that they have confidence in, and distribute or revoke these to and from other entities.Each entity has its own public-key base and can derive new knowledge by combining this knowledge with certificates signed with known keys. Each statement that is deduced or quoted within the system derives its support from original knowledge formed outside the system. When such original knowledge is removed, all statements that depended upon it are removed as well. Cyclic support is avoided through the use of support sets.We define different revocation reasons and show how they can be modelled as specific actions. Revocation by removal, by inactivation, and by negation are all included. By policy, negative statements are the strongest, and positive are the weakest. Collisions are avoided by removing the weaker statement and, when necessary, its support.Graph transformation rules are the chosen formalism. Rules are either interactive changes that can be applied by entities, or automatically applied deductions that keep the system sound and complete after the application of an interactive rule.We show that the proposed model is sound and complete with respect to our definition of a valid state.
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| 18. |
- 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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| 19. |
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| 20. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of plasmepsin I and II : x-ray crystal structure of inhibitor in complex with plasmepsin II
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:13, s. 4400-4409
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Tidskriftsartikel (refereegranskat)abstract
- New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.
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| 21. |
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| 22. |
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| 23. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II : Use of solid-phase synthesis to explore novel statine motifs
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:13, s. 3353-3366
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Tidskriftsartikel (refereegranskat)abstract
- Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Lindberg, Jimmy, et al.
(författare)
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Symmetric fluoro-substituted diol-based HIV protease inhibitors : Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy
- 2004
-
Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 271:22, s. 4594-4602
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 A resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluoro-substitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.
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| 28. |
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| 29. |
- Nilsson, Jonas, 1974-
(författare)
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Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule : Peptide Conjugates as Protein Actors
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes different aspects of protein interactions. Initially the function of peptides and their conjugates with small molecule inhibitors on the surface of Human Carbonic Anhydrase isoenzyme II (HCAII) is evaluated.The affinities for HCAII of the flexible, synthetic helix-loop-helix motif conjugated with a series of spacered inhibitors were measured by fluorescence spectroscopy and found in the best cases to be in the low nM range. Dissociation constants show considerable dependence on linker length and vary from 3000 nM for the shortest spacer to 40 nM for the longest with a minimum of 5 nM for a spacer with an intermediate length. A rationale for binding differences based on cooperativity is presented and supported by affinities as determined by fluorescence spectroscopy. Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance (HSQC) spectroscopic experiments with 15N-labeled HCAII were used for the determination of the site of interaction.The influence of peptide charge and hydrophobicity was evaluated by surface plasmon resonance experiments. Hydrophobic sidechain branching and, more pronounced, peptide charge was demonstrated to modulate peptide – HCAII binding interactions in a cooperative manner, with affinities spanning almost two orders of magnitude.Detailed synthesis of small molecule inhibitors in a general lead discovery library as well as a targeted library for inhibition of α-thrombin is described. For the lead discovery library 160 members emanate from two N4-aryl-piperazine-2-carboxylic acid scaffolds derivatized in two dimensions employing a combinatorial approach on solid support.The targeted library was based on peptidomimetics of the D-Phe-Pro-Arg showing the scaffolds cyclopropane-1R,2R-dicarboxylic acid and (4-amino-3-oxo-morpholin-2-yl)- acetic acid as proline isosters. Employing 4-aminomethyl-benzamidine as arginine mimic and different hydrophobic amines and electrophiles as D-phenylalanine mimics resulted in 34 compounds showing IC50 values for α-thrombin ranging more than three orders of magnitude with the best inhibitor showing an IC50 of 130 nM. Interestingly, the best inhibitors showed reversed stereochemistry in comparison with a previously reported series employing a 3-oxo-morpholin-2-yl-acetic acid scaffold.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Oscarsson, K, et al.
(författare)
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Solid phase assisted synthesis of HIV-1 protease inhibitors. Expedient entry to unsymmetrical substitution of a C-2 symmetric template
- 2000
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Ingår i: Canadian journal of chemistry (Print). - 0008-4042 .- 1480-3291. ; 78:6, s. 829-837
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Tidskriftsartikel (refereegranskat)abstract
- A solid phase synthesis has been developed leading up to unsymmetrical HIV-1 protease inhibitors that are not readily available by conventional solution phase chemistry (18a-g). To prepare these compounds the hydroxyl group of (1S,2R)-(-)-cis-1-phthalimido-2-indanol (3) was coupled to a Merrifield resin via a dihydropyrane linker. Cleavage of the phthalimido protecting group and reaction of the liberated amine with the bis-activated symmetrical diacid 15 resulted in the resin bound amide 16. Coupling of 16 with amino acids and amines followed by hydrolysis produced the desired unsymmetrical products 18a-g from which potent HIV-1 protease inhibitors were identified, e.g., 18e (k(i) = 0.1 nM), 18a (k(i) = 0.2 nM) and 18c (k(i) = 2 nM).
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| 34. |
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| 35. |
- Sandgren, Veronica, et al.
(författare)
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Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
- 2013
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Ingår i: Open Medicinal Chemistry Journal. - Bussum, Netherlands : Bentham Open. - 1874-1045. ; 7, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Novel BACE-1 inhibitors with a hydroxyethylene central core have been developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e., 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.
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| 36. |
- Sandgren, Veronica
(författare)
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Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the most common form of dementia, occurring in an estimated 24 million people worldwide. Accumulation of amyloid-b peptides leads to development of plaques in the brain, which eventually stimulates hyperphosphorylation of tau proteins leading to tangles. This is believed to play a crucial role in the pathology of AD. The amyloid-b peptides are formed when the amyloid precursor protein (APP) is cleaved first by the human aspartic protease BACE-1 and then by the protease g-secretase. BACE-1 catalyzes the ratelimiting step in this sequence, and hence it has emerged as an important therapeutic drug target.The research reported in this thesis is focused on the design and synthesis of BACE-1 inhibitors, where the synthetic work involves development of both acyclic and cyclic inhibitors. Initially, a series of linear inhibitors incorporating substituted cyclopentanes in the P2 position were synthesized and evaluated in an attempt to find a replacement for the widely used isophthalamide moiety, and this endeavor generated an inhibitor with activity in the nanomolar range. In the second study, a series of hydroxyethylene-based inhibitors with extended P1 substituents was synthesized and evaluated, which resulted in several truncated inhibitors also with activities in the nanomolar range. The third investigation targeted a series of P1-P3-linked hydroxyethylamine-based macrocyclic inhibitors and provided several highly potent compounds, however it did not deliver high cell permeability inhibitors. In addition, two inhibitors were co-crystallized with BACE-1 to provide X-ray crystal structures, which enabled analysis of the binding properties of these inhibitors. In the final study, the P2/P3 macrocyclic amide moiety and the P1-P3 ether oxygen bridge from the previous work were replaced with a keto functionality and a carbon, respectively, in an attempt to improve the permeability properties whilst maintaining the beneficial potencies of this class of macrocyclic inhibitors. The compounds synthesized did indeed display enhanced cell permeability properties, but this approach resulted in decreased potency.In short, this thesis presents several novel BACE-1 inhibitors, discusses the synthetic strategies, and reports biological data on the target compounds.
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| 37. |
- Sandgren, Veronica, et al.
(författare)
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Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors
- 2015
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Ingår i: Open Medicinal Chemistry Journal. - Bussum, Netherlands : Bentham Open. - 1874-1045. ; 9, s. 13-26
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Tidskriftsartikel (refereegranskat)abstract
- A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.
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| 38. |
- Sandgren, Veronica, et al.
(författare)
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Design and synthesis of novel macrocyclic BACE-1 inhibitors
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A series of arylketo-containing P1-P3 linked macrocyclic inhibitors was designed and synthesized and compared with a previously known and extensively used corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme and cell-based potencies. Several inhibitors displayed a substantial increase in Caco-2 cell-based permeability and notably also with retained potencies, showing that this approach might lead to centrally active BACE-1 inhibitors.
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| 39. |
- Sandgren, Veronica, et al.
(författare)
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Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A novel hydroxyethylene (HE) core structure with an O-methyl group in the P1´ position, previously reported by our group, has been further evaluated by introducing a substituted cyclopentane moiety in the P2 position. Results from earlier published work suggest that inhibitors containing the novel O-methyl HE core may result in inhibitors displaying promising potency against BACE-1 as well as selectivity towards cathepsin D. Furthermore, there is a general need for new and improved moieties in the P2 position for many BACE-1 inhibitors, e.g., the widely used substituted P2 isophthalamide structure often gives rise to inhibitors suffering from poor pharmacokinetics, including insufficient blood-brain barrier permeability. Different stereoisomers of the P2 cyclopentane moieties and a selection of P3 substituents have been examined. In addition, a macrocyclization study linking the P1 and P3 moieties was performed and biological results are discussed.
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| 40. |
- Sandgren, Veronica, et al.
(författare)
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Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core : Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
- 2012
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 29:14, s. 4377-4389
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Tidskriftsartikel (refereegranskat)abstract
- A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
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| 41. |
- Thorstensson, Fredrik, 1973-
(författare)
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Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.
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| 42. |
- Thorstensson, Fredrik, et al.
(författare)
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Synthesis of novel potent hepatitis C virus NS3 protease inhibitors : discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-L-hydroxyproline bioisostere
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:2, s. 827-838
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Tidskriftsartikel (refereegranskat)abstract
- Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.
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| 43. |
- Wachtmeister, J., et al.
(författare)
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Impact of the central hydroxyl groups on the activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid
- 2000
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Ingår i: Tetrahedron. - 0040-4020 .- 1464-5416. ; 56:20, s. 3219-3225
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Tidskriftsartikel (refereegranskat)abstract
- The influence of the central hydroxyl groups on the anti-viral activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid has been examined. L-Iditol was synthesized and used as a chiral precursor for the synthesis of the corresponding inhibitor with inverted configuration at C-3 and C-4. Key intermediates were 3,4-O-isopropylidene-L-iditol and the activated L-idaric acid succinimidyI ester. The configurations of the central hydroxyl groups required for optimal inhibition of the HIV-1 protease were determined to be the C-3R and C-4R, i.e. the L-manno-configuration. Three C2-symmetric inhibitors were converted to their thiocarbonates and reduced to provide the corresponding hydroxyethyl transition-state mimics. Deletion of the C-4 hydroxyl group in these inhibitors gave no further improvement in the anti-viral activity. (C) 2000 Published by Elsevier Science Ltd.
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| 44. |
- Wångsell, Fredrik, 1978-
(författare)
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Design and Synthesis of Serine and Aspartic Protease Inhibitors
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the design and synthesis of compounds that areintended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used N-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.
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| 45. |
- Wångsell, Fredrik, et al.
(författare)
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Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
- 2010
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:3, s. 870-882
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Tidskriftsartikel (refereegranskat)abstract
- We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxyl ethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the PI-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-I assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 Value of 3.1 nM.
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