Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.
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.
Shi
Yan
Y
Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
Li
Chi
C
O'Connor
Stephen P
SP
Zhang
Jing
J
Shi
Mengxiao
M
Bisaha
Sharon N
SN
Wang
Ying
Y
Sitkoff
Doree
D
Pudzianowski
Andrew T
AT
Huang
Christine
C
Klei
Herbert E
HE
Kish
Kevin
K
Yanchunas
Joseph
J
Liu
Eddie C-K
EC
Hartl
Karen S
KS
Seiler
Steve M
SM
Steinbacher
Thomas E
TE
Schumacher
William A
WA
Atwal
Karnail S
KS
Stein
Philip D
PD
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
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