Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates

…, CM McDonough, AM Naylor-Olsen…

Index: 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. Journal of Medicinal Chemistry, 1998 , vol. 41, # 23 p. 4466 - 4474

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Citation Number: 106

Abstract

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. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in ...