Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold.
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Bristol-Myers Squibb Research & Development, Hopewell, NJ 08534-5400, USA. scott.bolton@bms.com
Scott A
SA
Bolton
James C
JC
Sutton
Rushith
R
Anumula
Gregory S
GS
Bisacchi
Bruce
B
Jacobson
William A
WA
Slusarchyk
Uwe D
UD
Treuner
Shung C
SC
Wu
Guohua
G
Zhao
Zulan
Z
Pi
Steven
S
Sheriff
Rebecca A
RA
Smirk
Sharon
S
Bisaha
Daniel L
DL
Cheney
Anzhi
A
Wei
William A
WA
Schumacher
Karen S
KS
Hartl
Eddie
E
Liu
Robert
R
Zahler
Steven M
SM
Seiler
D001550:Benzamidines; D002264:Carboxylic Acids / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001550:Benzamidines; D002264:Carboxylic Acids; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa
2-Aminoisoquinoline; Factor VIIa; Inhibition