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Discovery of a potent and selective small molecule hGPR91 antagonist.
Bioorg Med Chem Lett ; 21(12): 3596-602, 2011 Jun 15.
Article em En | MEDLINE | ID: mdl-21571530
ABSTRACT
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 µM)-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 5 g (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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Acoplados a Proteínas G / Bibliotecas de Moléculas Pequenas / Descoberta de Drogas Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Acoplados a Proteínas G / Bibliotecas de Moléculas Pequenas / Descoberta de Drogas Idioma: En Ano de publicação: 2011 Tipo de documento: Article