title: Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.
abstract: We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
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: Chi
authors.initials: C
authors.lastname: Li
authors.forename: Stephen P
authors.initials: SP
authors.lastname: O'Connor
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Bisaha
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Doree
authors.initials: D
authors.lastname: Sitkoff
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Pudzianowski
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
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: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D055808:Drug Discovery; D065427:Factor Xa Inhibitors; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C546974:6-(dimethylcarbamoyl)nicotinoyl guanidine; D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D065427:Factor Xa Inhibitors; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human