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ACS Med Chem Lett. 2015 Mar 18;6(5):513-7. doi: 10.1021/ml500514w. eCollection 2015 May 14.

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

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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.


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).


antagonist; sstr3; tetrahydro-β-carboline; type 2 diabetes

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