Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
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.
Shi
Yan
Y
Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
Zhang
Jing
J
Shi
Mengxiao
M
O'Connor
Stephen P
SP
Bisaha
Sharon N
SN
Li
Chi
C
Sitkoff
Doree
D
Pudzianowski
Andrew T
AT
Chong
Saeho
S
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
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
C545361:BMS 269223; D001572:Benzofurans; D006146:Guanidines; D007769:Lactams; D008024:Ligands; D000990:Antithrombin III; D013890:Thiourea; C004711:dicyandiamido