Benzo[b]thiophene-2-carboxamide derivatives as potent urotensin-II receptor antagonists.
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.
Bio & 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. Electronic address: chemlcj@krict.re.kr.
Chae Jo
CJ
Lim
Bio & 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.
Seong Eun
SE
Woo
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Chemistry, Mokpo National University, Muan-gun, Jeonnam 58554, Republic of Korea.
Su Ik
SI
Ko
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea.
Byung Ho
BH
Lee
Bio & 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.
Kwang-Seok
KS
Oh
Bio & 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. Electronic address: kyyi@krict.re.kr.
Kyu Yang
KY
Yi
D006801:Humans; D020128:Inhibitory Concentration 50; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
D043562:Receptors, G-Protein-Coupled; D013876:Thiophenes; C121697:UTS2R protein, human
Antagonists; Benzo[b]thiophene carboxamide; Cardiovascular disease; Urotensin-II receptor