Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.
A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.
Feng
D M
DM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Gardell
S J
SJ
Lewis
S D
SD
Bock
M G
MG
Chen
Z
Z
Freidinger
R M
RM
Naylor-Olsen
A M
AM
Ramjit
H G
HG
Woltmann
R
R
Baskin
E P
EP
Lynch
J J
JJ
Lucas
R
R
Shafer
J A
JA
Dancheck
K B
KB
Chen
I W
IW
Mao
S S
SS
Krueger
J A
JA
Hare
T R
TR
Mulichak
A M
AM
Vacca
J P
JP
D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D007700:Kinetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000991:Antithrombins; D004151:Dipeptides; D011725:Pyridines; D013917:Thrombin