P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

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 μM, t 1/2  = 4.5 h).