title: Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
abstract: The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Stephen P
authors.initials: SP
authors.lastname: O'Connor
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Bisaha
authors.forename: Chi
authors.initials: C
authors.lastname: Li
authors.forename: Doree
authors.initials: D
authors.lastname: Sitkoff
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Pudzianowski
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Joseph
authors.initials: J
authors.lastname: Yanchunas
authors.forename: Eddie C-K
authors.initials: EC
authors.lastname: Liu
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hartl
authors.forename: Steve M
authors.initials: SM
authors.lastname: Seiler
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Steinbacher
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Karnail S
authors.initials: KS
authors.lastname: Atwal
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000990:Antithrombin III / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004285:Dogs; D006146:Guanidines / Q000737:chemistry*; D000882:Haplorhini; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
chemical_list: C545361:BMS 269223; D001572:Benzofurans; D006146:Guanidines; D007769:Lactams; D008024:Ligands; D000990:Antithrombin III; D013890:Thiourea; C004711:dicyandiamido