deCODE Chemistry Inc.

Woodridge, IL, United States

deCODE Chemistry Inc.

Woodridge, IL, United States
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Families Of Spinal Muscular Atrophy, Gurney and deCODE Chemistry Inc. | Date: 2017-01-25

2,4-Diaminoquinazolines of formulae I-IV and VI

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 | Year: 2010

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.

Sandanayaka V.,deCODE Chemistry Inc. | Mamat B.,DeCODE Genetics Inc. | Bhagat N.,deCODE Chemistry Inc. | Bedell L.,deCODE Chemistry Inc. | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA4 hydrolase (LTA4H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA4H binding mode for analogs from the piperidine series. © 2010.

The EP3 receptor on the platelet mediates prostaglandin E 2 potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP3 receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis. © 2009 American Chemical Society.

Families Of Spinal Muscular Atrophy, deCODE Chemistry Inc. and Gurney | Date: 2012-10-24

2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI)

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 | Year: 2010

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.

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 | Year: 2010

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.

Singh J.,deCODE Chemistry Inc. | Kiselyov A.S.,deCODE Chemistry Inc.
Drugs of the Future | Year: 2010

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.

Polozov A.M.,deCODE Chemistry Inc. | Hategan G.,deCODE Chemistry Inc. | Cao H.,deCODE Chemistry Inc. | Kiselyov A.S.,deCODE Chemistry Inc. | And 2 more authors.
Tetrahedron Letters | Year: 2010

Isosteric replacement of the α,β-unsaturated amide at the C-7 position of indoles with a diverse set of five-membered amino-heterocycles including isoxazole, oxadiazole, thiadiazole and pyrazole followed by subsequent derivatization of the heterocyclic amino group to yield amides, sulfonamides and phosphoramides is described. Distinctive features of these procedures include the versatility and robust nature of the synthetic steps along with the high yields of the targeted molecules. © 2009 Elsevier Ltd. All rights reserved.

Zeller W.,deCODE Chemistry Inc. | Kiselyov A.S.,deCODE Chemistry Inc. | Singh J.,deCODE Chemistry Inc.
Tetrahedron Letters | Year: 2010

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.

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