title: Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring.
abstract: The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@spcorp.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Martin
authors.initials: M
authors.lastname: Clasby
authors.forename: Darío
authors.initials: D
authors.lastname: Doller
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Hsingan
authors.initials: H
authors.lastname: Tsai
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Agans-Fantuzzi
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: George C
authors.initials: GC
authors.lastname: Boykow
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lunn
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000925:Anticoagulants; D005663:Furans; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; C048172:himbacine