Discovery of a potent and selective small molecule hGPR91 antagonist

被引：64

作者：

Bhuniya, Debnath ^{[1
]}

Umrani, Dhananjay ^{[1
]}

Dave, Bhavesh ^{[1
]}

Salunke, Deepak ^{[1
]}

Kukreja, Gagan ^{[1
]}

Gundu, Jayasagar ^{[1
]}

Naykodi, Minakshi ^{[1
]}

Shaikh, Nadim S. ^{[1
]}

Shitole, Prasad ^{[1
]}

Kurhade, Santosh ^{[1
]}

De, Siddhartha ^{[1
]}

Majumdar, Sreemita ^{[1
]}

Reddy, Srinivasa B. ^{[1
]}

Tambe, Suhas ^{[1
]}

Shejul, Yogesh ^{[1
]}

Chugh, Anita ^{[1
]}

Palle, Venkata P. ^{[1
]}

Mookhtiar, Kasim A. ^{[1
]}

Cully, Doris ^{[2
]}

Vacca, Joseph ^{[2
]}

Chakravarty, Prasun K. ^{[2
]}

Nargund, Ravi P. ^{[2
]}

Wright, Samuel D. ^{[2
]}

Graziano, Michael P. ^{[2
]}

Singh, Sheo B. ^{[2
]}

Roy, Sophie ^{[2
]}

Cai, Tian-Quan ^{[2
]}

机构：

[1] Advinus Therapeut, Drug Discovery Facil, Pune 411057, Maharashtra, India

[2] Merck Res Labs, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 12期

关键词：

GPR91; Succinate; hGPR91; antagonist; Structure-activity relationship; Pharmacodynamic effect; SUCCINATE RECEPTOR GPR91; RENIN RELEASE; HIGH GLUCOSE; ACTIVATION;

D O I：

10.1016/j.bmcl.2011.04.091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3596 / 3602

页数：7

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