Discovery of a potent and selective small molecule hGPR91 antagonist
Discovery of a potent and selective small molecule hGPR91 antagonist
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DOI：
10.1016/j.bmcl.2011.04.091
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发表时间：
2011-06-15
影响因子：
2.7
通讯作者：
Cai, Tian-Quan
中科院分区：
文献类型：
--
作者：
Bhuniya, Debnath;Umrani, Dhananjay;Cai, Tian-Quan
GPR 91是一种7 TM G蛋白偶联受体，最近已被琥珀酸作为其内源性配体去磷酸化。目前的文献表明GPR 91在多种病理生理学中起作用，包括肾性高血压、自身免疫性疾病和视网膜血管生成。从小分子开始高通量筛选命中1（hGPR 91 IC（50）：0.8 μ M）-最初在Merck的缓激肽B（1）受体（BK（1）R）项目中合成，系统的结构-活性关系研究使我们发现了有效的和选择性的hGPR 91拮抗剂，例如2c、4c和5g（IC（50）：7-35 nM;>1000倍选择性针对hGPR 99，最接近相关的GPCR; > 100倍选择性在药物基质筛选中）。该初步工作还导致鉴定了两种结构不同且口服生物可利用的先导化合物：5g（%F：26）和7 e（IC（50）：180 nM;对hGPR 99的选择性> 100倍; %F：87）。开发了大鼠药效学测定，以使用琥珀酸盐诱导的血压升高来表征体内拮抗剂。使用两种代表性拮抗剂2c和4c，随后使用设计的药效学测定证明了GPR 91靶标接合。(C)2011爱思唯尔有限公司版权所有。
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.