1z71

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Template:STRUCTURE 1z71

thrombin and P2 pyridine N-oxide inhibitor complex structure

Overview

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).

About this Structure

1Z71 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold., Nantermet PG, Burgey CS, Robinson KA, Pellicore JM, Newton CL, Deng JZ, Selnick HG, Lewis SD, Lucas BJ, Krueger JA, Miller-Stein C, White RB, Wong B, McMasters DR, Wallace AA, Lynch JJ Jr, Yan Y, Chen Z, Kuo L, Gardell SJ, Shafer JA, Vacca JP, Lyle TA, Bioorg Med Chem Lett. 2005 Jun 2;15(11):2771-5. PMID:15911253 Page seeded by OCA on Sat May 3 17:15:27 2008