C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption.
1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.
Isaacs
R C
RC
Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Cutrona
K J
KJ
Newton
C L
CL
Sanderson
P E
PE
Solinsky
M G
MG
Baskin
E P
EP
Chen
I W
IW
Cooper
C M
CM
Cook
J J
JJ
Gardell
S J
SJ
Lewis
S D
SD
Lucas
R J
RJ
Lyle
E A
EA
Lynch
J J
JJ
Naylor-Olsen
A M
AM
Stranieri
M T
MT
Vastag
K
K
Vacca
J P
JP
D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013424:Sulfanilamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology
D000991:Antithrombins; C116624:L 374087; C116663:L 375052; D011725:Pyridines; D011728:Pyridones; D013424:Sulfanilamides; D013449:Sulfonamides