title: Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors.
abstract: A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400 Princeton, NJ 08542-5400, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wacker
authors.forename: Irina C
authors.initials: IC
authors.lastname: Jacobson
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Ming Y
authors.initials: MY
authors.lastname: He
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Steven
authors.initials: S
authors.lastname: Bai
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000990:Antithrombin III / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D018938:Caco-2 Cells; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D007211:Indoles; D011720:Pyrazoles; C031280:pyrazole; C057812:indoline; D000990:Antithrombin III