title: A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties.
abstract: We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
authors.affiliation: Department of Medicinal Chemistry, Cardiovascular Disease, or Drug Discovery Support, Boehringer Ingelheim Pharmaceutical, Inc, Ridgefield, CT 06877, United States. nmoss@rdg.boehringer-ingelheim.com
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
authors.forename: Younggi
authors.initials: Y
authors.lastname: Choi
authors.forename: Derek
authors.initials: D
authors.lastname: Cogan
authors.forename: Adam
authors.initials: A
authors.lastname: Flegg
authors.forename: Andreas
authors.initials: A
authors.lastname: Kahrs
authors.forename: Pui
authors.initials: P
authors.lastname: Loke
authors.forename: Orietta
authors.initials: O
authors.lastname: Meyn
authors.forename: Raj
authors.initials: R
authors.lastname: Nagaraja
authors.forename: Spencer
authors.initials: S
authors.lastname: Napier
authors.forename: Ashley
authors.initials: A
authors.lastname: Parker
authors.forename: J
authors.initials: J
authors.lastname: Thomas Peterson
authors.forename: Philip
authors.initials: P
authors.lastname: Ramsden
authors.forename: Christopher
authors.initials: C
authors.lastname: Sarko
authors.forename: Donna
authors.initials: D
authors.lastname: Skow
authors.forename: Josh
authors.initials: J
authors.lastname: Tomlinson
authors.forename: Heather
authors.initials: H
authors.lastname: Tye
authors.forename: Mark
authors.initials: M
authors.lastname: Whitaker
mesh_terms: D000818:Animals; D001665:Binding Sites; D008297:Male; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000145:classification / Q000493:pharmacokinetics*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists