Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors.: Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1N-benzylamides

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable PI N-benzylamide thrombin inhibitors. An expedited investigation of the PI SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation. (C) 2003 Elsevier Science Ltd. All rights reserved.