强效、选择性促生长激素释放激素受体3拮抗剂MK-1421作为2型糖尿病开发候选药物的发现。
Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.
作者信息
Shah Shrenik K, He Shuwen, Guo Liangqin, Truong Quang, Qi Hongbo, Du Wu, Lai Zhong, Liu Jian, Jian Tianying, Hong Qingmei, Dobbelaar Peter, Ye Zhixiong, Sherer Edward, Feng Zhe, Yu Yang, Wong Frederick, Samuel Koppara, Madiera Maria, Karanam Bindhu V, Reddy Vijay B, Mitelman Stan, Tong Sharon X, Chicchi Gary G, Tsao Kwei-Lan, Trusca Dorina, Feng Yue, Wu Margaret, Shao Qing, Trujillo Maria E, Eiermann George J, Li Cai, Pachanski Michele, Fernandez Guillermo, Nelson Donald, Bunting Patricia, Morissette Pierre, Volksdorf Sylvia, Kerr Janet, Zhang Bei B, Howard Andrew D, Zhou Yun-Ping, Pasternak Alexander, Nargund Ravi P, Hagmann William K
机构信息
Departments of Medicinal Chemistry, Chemistry Modeling and Infomatics, Drug Metabolism and Pharmacokinetics, and Diabetes Research, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Department of Safety Assessment, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
出版信息
ACS Med Chem Lett. 2015 Mar 18;6(5):513-7. doi: 10.1021/ml500514w. eCollection 2015 May 14.
The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).
咪唑基-四氢-β-咔啉类促生长激素释放激素受体3拮抗剂在小鼠血糖波动模型中已显示出疗效，可能具有作为2型糖尿病治疗药物的潜力。该类中的首个候选药物在口服遥测心血管（CV）犬中引起了不可接受的QTc间期延长。在此，我们描述了我们为鉴定出无心血管效应的可接受候选药物所做的努力。这些努力导致鉴定出了(1R,3R)-3-(4-(5-氟吡啶-2-基)-1H-咪唑-2-基)-1-(1-乙基-吡唑-4-基)-1-(3-甲基-1,3,4-恶二唑-3H-2-酮-5-基)-2,3,4,9-四氢-1H-β-咔啉（17e，MK-1421）。
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