| 1. |
- Andaloussi, Mounir, et al.
(author)
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Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
- 2011
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 54:14, s. 4964-4976
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Journal article (peer-reviewed)abstract
- The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
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| 2. |
- Andappan, Murugaiah M. S., et al.
(author)
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From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
- 2012
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:5, s. 2265-2278
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Journal article (peer-reviewed)abstract
- A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
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| 3. |
- Andersson, C David, et al.
(author)
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Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
- 2012
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:17, s. 7706-7718
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Journal article (peer-reviewed)abstract
- The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.
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| 4. |
- Andersson, C. David, et al.
(author)
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Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors
- 2013
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:19, s. 7615-7624
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Journal article (peer-reviewed)abstract
- The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
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| 5. |
- Andersson, Hanna, 1979-, et al.
(author)
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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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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:22, s. 8059-8071
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Journal article (peer-reviewed)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. |
- Andersson, Hanna, 1979-, et al.
(author)
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Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
- 2011
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51, s. 3779-3792
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Journal article (peer-reviewed)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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| 7. |
- Aplander, Karolina, et al.
(author)
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Molecular wipes : application to epidemic keratoconjuctivitis
- 2011
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In: Journal of Medicinal Chemistry. - Easton, Pa. : American Chemical Society. - 0022-2623 .- 1520-4804. ; 54:19, s. 6670-6675
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Journal article (peer-reviewed)abstract
- Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 mu M) and Ad infectivity (IC(50) = 0.7 mu M). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.
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| 8. |
- Araújo, Ana Catarina, et al.
(author)
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Sugar-Based Enantiomeric and Conformationally Constrained Pyrrolo[2,1-c][1,4]-Benzodiazepines as Potential GABA(A) Ligands
- 2011
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 54:5, s. 1266-1275
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Journal article (peer-reviewed)abstract
- Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic D- or L-proline analogues containing a D- or L-fructose moiety was developed. The L-fructose moiety was obtained by using a new synthetic pathway starting from L-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that D- and L.-fructose-based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by compounds have increased the understanding of the differential recognition receptor. participating in the binding event. Finally, these of (M)-/(P)-helical benzodiazepines on GABA(A) receptor.
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| 9. |
- Auzzas, Luciana, et al.
(author)
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Non-natural macrocyclic inhibitors of histone deacetylases : design, synthesis, and activity
- 2010
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In: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 53:23, s. 8387-8399
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Journal article (peer-reviewed)abstract
- Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.
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| 10. |
- Barlind, Jonas G, et al.
(author)
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Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687)
- 2012
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:23, s. 10610-10629
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Journal article (peer-reviewed)abstract
- A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
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