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Kiselyov A.S.,deCODE Chemistry Inc. | Semenova M.N.,Russian Academy of Sciences | Chernyshova N.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Leitao A.,University of New Mexico | And 10 more authors.
European Journal of Medicinal Chemistry

A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site. © 2010 Elsevier Masson SAS. All rights reserved. Source

Singh J.,deCODE Chemistry Inc. | Kiselyov A.S.,deCODE Chemistry Inc.
Drugs of the Future

Current antiplatelet therapies offer significant benefits for the treatment of patients at risk for recurrent cardiovascular events. However, clinical data suggest that many of these agents lead to an increased risk of severe or fatal hemorrhage by affecting general platelet function. It has been suggested that targeting the inflammatory component of the disease instead may address this issue. Human genetic data from peripheral arterial occlusive disease (PAOD), heart attack and stroke converged on the identification of the EP3 receptor as a target, linking variations in the gene encoding EP3 to an increased risk for the disease. Several small-molecule EP3 antagonists employed either as monotherapy or in combination with clopidogrel and aspirin have been shown to inhibit platelet aggregation at the site of lesions in the vasculature, without increasing bleeding time. This suggests that targeting the inflammatory mechanism of arterial thrombosis mediated by the prostaglandin E2 (PGE2)-EP3 receptor system may lead to a new generation of antiplatelet drugs with an enhanced safety and efficacy profile. Copyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved. Source

Sheremetev A.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Dmitriev D.E.,RAS N. D. Zelinsky Institute of Organic Chemistry | Lagutina N.K.,RAS N. D. Zelinsky Institute of Organic Chemistry | Raihstat M.M.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 4 more authors.
Mendeleev Communications

A series of new furazan (1,2,5-oxadiazole) derivatives based on structural overlap with combretastatin have been synthesized. Targeted molecules were evaluated using the sea urchin embryo assay; several agents demonstrated 1-4 μmol dm-3 antiproliferative activity in this in vivo model. © 2010 Mendeleev Communications. All rights reserved. Source

Zeller W.,deCODE Chemistry Inc. | Kiselyov A.S.,deCODE Chemistry Inc. | Singh J.,deCODE Chemistry Inc.
Tetrahedron Letters

Regiospecific construction of 3-alkyl-4-hydroxybenzimidazoles is detailed. The synthetic route involves a novel O- to N-acyl transfer reaction to address the observed exclusive O-acylation of 2-amino-3-nitrophenol starting material. This efficient route provides the targeted 3-alkyl-4-hydroxybenzimidazoles in good yields, in five steps, without the use of chromatographic purification. These key intermediates were subsequently elaborated, as shown, to provide acylsulfonamide-derived potent EP3 receptor antagonists. © 2010 Elsevier Ltd. All rights reserved. Source

Burgin A.B.,deCODE Biostructures Inc. | Magnusson O.T.,DeCODE Genetics Inc. | Singh J.,deCODE Chemistry Inc. | Witte P.,deCODE Biostructures Inc. | And 8 more authors.
Nature Biotechnology

Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (Imax∼ 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit. © 2010 Nature America, Inc. All rights reserved. Source

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