ABSTRACT
In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).
Subject(s)
Antithrombins/chemistry , Pyrimidines/chemistry , Hydrogen Bonding , Models, Molecular , Molecular MimicryABSTRACT
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 P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemistry , Thrombin/antagonists & inhibitors , Animals , Biological Availability , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Dogs , Half-Life , Humans , In Vitro Techniques , Injections, Intravenous , Macaca mulatta , Microsomes, Liver/metabolism , Models, Molecular , Oxides/chemistry , Rats , Solubility , Structure-Activity Relationship , Thrombosis/chemically induced , Thrombosis/drug therapyABSTRACT
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
