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Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.

ABSTRACT: The imidazolyl-tetrahydro-?-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-?-carboline (17e, MK-1421).

SUBMITTER: Shah SK 

PROVIDER: S-EPMC4434471 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.

Shah Shrenik K SK   He Shuwen S   Guo Liangqin L   Truong Quang Q   Qi Hongbo H   Du Wu W   Lai Zhong Z   Liu Jian J   Jian Tianying T   Hong Qingmei Q   Dobbelaar Peter P   Ye Zhixiong Z   Sherer Edward E   Feng Zhe Z   Yu Yang Y   Wong Frederick F   Samuel Koppara K   Madiera Maria M   Karanam Bindhu V BV   Reddy Vijay B VB   Mitelman Stan S   Tong Sharon X SX   Chicchi Gary G GG   Tsao Kwei-Lan KL   Trusca Dorina D   Feng Yue Y   Wu Margaret M   Shao Qing Q   Trujillo Maria E ME   Eiermann George J GJ   Li Cai C   Pachanski Michele M   Fernandez Guillermo G   Nelson Donald D   Bunting Patricia P   Morissette Pierre P   Volksdorf Sylvia S   Kerr Janet J   Zhang Bei B BB   Howard Andrew D AD   Zhou Yun-Ping YP   Pasternak Alexander A   Nargund Ravi P RP   Hagmann William K WK  

ACS medicinal chemistry letters 20150318 5

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-imidazo  ...[more]

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