C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption

R C Isaacs; K J Cutrona; C L Newton; P E Sanderson; M G Solinsky; E P Baskin; I W Chen; C M Cooper; J J Cook; S J Gardell; S D Lewis; R J Lucas Jr; E A Lyle; J J Lynch Jr; A M Naylor-Olsen; M T Stranieri; K Vastag; J P Vacca

doi:10.1016/s0960-894x(98)00297-2

C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption

Bioorg Med Chem Lett. 1998 Jul 7;8(13):1719-24. doi: 10.1016/s0960-894x(98)00297-2.

Authors

R C Isaacs¹, K J Cutrona, C L Newton, P E Sanderson, M G Solinsky, E P Baskin, I W Chen, C M Cooper, J J Cook, S J Gardell, S D Lewis, R J Lucas Jr, E A Lyle, J J Lynch Jr, A M Naylor-Olsen, M T Stranieri, K Vastag, J P Vacca

Affiliation

¹ Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

PMID: 9873422
DOI: 10.1016/s0960-894x(98)00297-2

Abstract

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.

MeSH terms

Administration, Oral
Animals
Antithrombins / administration & dosage
Antithrombins / chemistry*
Antithrombins / pharmacokinetics*
Biological Availability
Dogs
Pyridines / chemistry
Pyridines / pharmacokinetics
Pyridines / pharmacology
Pyridones / chemistry*
Pyridones / pharmacokinetics*
Pyridones / pharmacology
Rats
Sulfanilamides / chemistry
Sulfanilamides / pharmacokinetics
Sulfanilamides / pharmacology
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics*
Sulfonamides / pharmacology

Substances

Antithrombins
L 374087
L 375052
Pyridines
Pyridones
Sulfanilamides
Sulfonamides