title: Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists.
abstract: The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Chae Jo
authors.initials: CJ
authors.lastname: Lim
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Seung Ae
authors.initials: SA
authors.lastname: Oh
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.affiliation: Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: kyyi@krict.re.kr.
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
mesh_terms: D000818:Animals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: C000600089:1-(2-(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)ethyl)-3-(thieno(3,2-b)pyridin-7-yl)urea; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D013876:Thiophenes; C121697:UTS2R protein, human; C446540:thienopyridine; D014508:Urea
keywords: Antagonists; Cardiovascular disease; Thieno[3,2-b]pyridinyl urea; Urotensin-II receptor