Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors.
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.
Varnes
Jeffrey G
JG
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400 Princeton, NJ 08542-5400, USA.
Wacker
Dean A
DA
Jacobson
Irina C
IC
Quan
Mimi L
ML
Ellis
Christopher D
CD
Rossi
Karen A
KA
He
Ming Y
MY
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Bai
Steven
S
He
Kan
K
Lam
Patrick Y S
PY
Wexler
Ruth R
RR
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
D065427:Factor Xa Inhibitors; D007211:Indoles; D011720:Pyrazoles; C031280:pyrazole; C057812:indoline; D000990:Antithrombin III