GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 mu M)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; > 100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; > 100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay. (C) 2011 Elsevier Ltd. All rights reserved.
机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
Cao, S
Qian, XH
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Qian, XH
Song, GH
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机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
Song, GH
Huang, QC
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机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
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Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Euroscreen Inc., BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Gonzalez N.S.
Communi D.
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Hannedouche S.
Boeynaems J.-M.
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Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Laboratory of Medical Chemistry, Erasme Hospital, Free University of Brussels, Brussels
Chimie Médicale, Erasme Hospital, 1070 BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
Cao, S
Qian, XH
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Qian, XH
Song, GH
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机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
Song, GH
Huang, QC
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机构:Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China
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Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Euroscreen Inc., BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Gonzalez N.S.
Communi D.
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Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
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Hannedouche S.
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Euroscreen Inc., BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Hannedouche S.
Boeynaems J.-M.
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机构:
Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels
Laboratory of Medical Chemistry, Erasme Hospital, Free University of Brussels, Brussels
Chimie Médicale, Erasme Hospital, 1070 BrusselsInstitute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels