Garnsey Michelle R, Smith Aaron C, Polivkova Jana, Arons Autumn L, Bai Guoyun, Blakemore Caroline, Boehm Markus, Buzon Leanne M, Campion Sarah N, Cerny Matthew, Chang Shiao-Chi, Coffman Karen, Farley Kathleen A, Fonseca Kari R, Ford Kristen K, Garren Jeonifer, Kong Jimmy X, Koos Martin R M, Kung Daniel W, Lian Yajing, Li Monica M, Li Qifang, Martinez-Alsina Luis A, O'Connor Rebecca, Ogilvie Kevin, Omoto Kiyoyuki, Raymer Brian, Reese Matthew R, Ryder Tim, Samp Lacey, Stevens Kimberly A, Widlicka Daniel W, Yang Qingyi, Zhu Kaicheng, Fortin Jean-Philippe, Sammons Matthew F
Pfizer, Incorporated, Cambridge, Massachusetts 02139, United States.
Pfizer, Incorporated, Groton, Connecticut 06340, United States.
J Med Chem. 2023 Mar 9;66(5):3195-3211. doi: 10.1021/acs.jmedchem.2c02012. Epub 2023 Feb 19.
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate . Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.
黑皮质素-4受体（MC4R）是一种在中枢表达的A类G蛋白偶联受体（GPCR），在食欲和食物摄入调节中起关键作用。MC4R信号传导缺陷会导致人类食欲亢进和体重增加。在因潜在疾病导致的厌食或恶病质情况下，MC4R信号传导的拮抗作用有可能减轻食欲下降和体重减轻。在此，我们报告通过集中的命中化合物鉴定工作鉴定出一系列口服生物可利用的小分子MC4R拮抗剂，并对这些拮抗剂进行优化以提供临床候选药物。引入螺环构象限制能够同时优化MC4R活性和药物代谢动力学（ADME）特性，同时避免在早期系列先导化合物中观察到的人醚-去极化相关基因（hERG）活性代谢物的产生。化合物 是一种强效且选择性的MC4R拮抗剂，在老年恶病质大鼠模型中具有强大的功效，并且已进入临床试验阶段。
