Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position

D M Feng; S J Gardell; S D Lewis; M G Bock; Z Chen; R M Freidinger; A M Naylor-Olsen; H G Ramjit; R Woltmann; E P Baskin; J J Lynch; R Lucas; J A Shafer; K B Dancheck; I W Chen; S S Mao; J A Krueger; T R Hare; A M Mulichak; J P Vacca

doi:10.1021/jm970493r

Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position

J Med Chem. 1997 Nov 7;40(23):3726-33. doi: 10.1021/jm970493r.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

PMID: 9371237
DOI: 10.1021/jm970493r

Abstract

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.

MeSH terms

Administration, Oral
Animals
Antithrombins / chemical synthesis*
Antithrombins / pharmacokinetics
Antithrombins / pharmacology*
Biological Availability
Crystallography, X-Ray
Dipeptides / chemical synthesis*
Dipeptides / pharmacokinetics
Dipeptides / pharmacology*
Dogs
Kinetics
Pyridines / chemical synthesis*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Rats
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*
Thrombin / metabolism

Substances

Antithrombins
Dipeptides
Pyridines
Thrombin