L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor.
Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.
Sanderson
P E
PE
Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Cutrona
K J
KJ
Dorsey
B D
BD
Dyer
D L
DL
McDonough
C M
CM
Naylor-Olsen
A M
AM
Chen
I W
IW
Chen
Z
Z
Cook
J J
JJ
Gardell
S J
SJ
Krueger
J A
JA
Lewis
S D
SD
Lin
J H
JH
Lucas
B J
BJ
Lyle
E A
EA
Lynch
J J
JJ
Stranieri
M T
MT
Vastag
K
K
Shafer
J A
JA
Vacca
J P
JP
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002712:Chlorides; D018360:Crystallography, X-Ray; D004285:Dogs; D005290:Ferric Compounds; D007700:Kinetics; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy; D014357:Trypsin / Q000378:metabolism
D000925:Anticoagulants; D002712:Chlorides; D005290:Ferric Compounds; C116625:L 373890; C116624:L 374087; D011728:Pyridones; D013449:Sulfonamides; D014357:Trypsin; D013917:Thrombin; C024555:ferric chloride