- P2 pyridine N-oxide thrombin inhibitors: A novel peptidomimetic scaffold
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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 (Cmax = 2.6 μM, t 1/2 = 4.5 h).
- Nantermet, Philippe G.,Burgey, Christopher S.,Robinson, Kyle A.,Pellicore, Janetta M.,Newton, Christina L.,Deng, James Z.,Selnick, Harold G.,Lewis, S. Dale,Lucas, Bobby J.,Krueger, Julie A.,Miller-Stein, Cynthia,White, Rebecca B.,Wong, Bradley,McMasters, Daniel R.,Wallace, Audrey A.,Lynch Jr., Joseph J.,Yan, Youwei,Chen, Zhongguo,Kuo, Lawrence,Gardell, Stephen J.,Shafer, Jules A.,Vacca, Joseph P.,Lyle, Terry A.
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p. 2771 - 2775
(2007/10/03)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: wherein R1 is, for example, hydrogen, Cl, or cyano, and R2 is, for example, hydrogen,
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- Efficacious, orally bioavailable thrombin inhibitors based on 3- aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates
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We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3- sulfonylaminopyridinone core.
- Sanderson, Philip E. J.,Lyle, Terry A.,Cutrona, Kellie J.,Dyer, Dona L.,Dorsey, Bruce D.,McDonough, Colleen M.,Naylor-Olsen, Adel M.,Chen, I.-Wu,Chen, Zhongguo,Cook, Jacquelynn J.,Cooper, Carolyn M.,Gardell, Stephen J.,Hare, Timothy R.,Krueger, Julie A.,Lewis, S. Dale,Lin, Jiunn H.,Lucas Jr., Bobby J.,Lyle, Elizabeth A.,Lynch Jr., Joseph J.,Stranieri, Maria T.,Vastag, Kari,Yan, Youwei,Shafer, Jules A.,Vacca, Joseph P.
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p. 4466 - 4474
(2007/10/03)
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- PYRIDINONE THROMBIN INHIBITORS
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions and have the following structure: STR1 for example: STR2
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