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Published on: August 18, 2014
Benzo[b]thiophene-2-carboxamide derivatives as potent urotensin-II receptor antagonists
Chae Jo Lim1, Seong Eun Woo1, Su Ik Ko2
1Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Abstract:
Members of a series of benzo[b]thiophene-2-carboxamide derivatives, possessing an N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl) group, were synthesized and evaluated as urotensin-II receptor antagonists. The results show that these substances have potent UT binding affinities. Observations made in a systematic SAR investigation of the effects of a variety of substituents (R(1) and R(2)) at the 5- and 6-positions in the benzo[b]thiophene-2-carboxamide moiety on UT binding affinities led to identification of the 5-cyano analog 7f as a highly potent UT antagonist with an IC50 value of 25nM. Despite having a good metabolic stability, 7f is a potent inhibitor of CYP isozyme and displays an unsuitable PK profile.
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