Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Kleanthous, Savvas; Borthwick, Alan D; Brown, David; Burns-Kurtis, Cynthia L; Campbell, Matthew; Chaudry, Laiq; Chan, Chuen; Clarte, Marie-Olive; Convery, Máire A; Harling, John D; Hortense, Eric; Irving, Wendy R; Irvine, Stephanie; Pateman, Anthony J; Patikis, Angela N; Pinto, Ivan L; Pollard, Derek R; Roethka, Theresa J; Senger, Stefan; Shah, Gita P; Stelman, Gary J; Toomey, John R; Watson, Nigel S; West, Robert I; Whittaker, Caroline; Zhou, Ping; Young, Robert J

Kleanthous, Savvas; Borthwick, Alan D; Brown, David; Burns-Kurtis, Cynthia L; Campbell, Matthew; Chaudry, Laiq; Chan, Chuen; Clarte, Marie-Olive; Convery, Máire A; Harling, John D; Hortense, Eric; Irving, Wendy R; Irvine, Stephanie; Pateman, Anthony J; Patikis, Angela N; Pinto, Ivan L; Pollard, Derek R; Roethka, Theresa J; Senger, Stefan; Shah, Gita P; Stelman, Gary J; Toomey, John R; Watson, Nigel S; West, Robert I; Whittaker, Caroline; Zhou, Ping; Young, Robert J.

Afiliación

Kleanthous S; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

Bioorg Med Chem Lett ; 20(2): 618-22, 2010 Jan 15.

Article en En | MEDLINE | ID: mdl-20006499

RESUMEN

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Asunto(s)

Anticoagulantes/química; Factor X/antagonistas & inhibidores; Pirrolidinonas/química; Anticoagulantes/síntesis química; Anticoagulantes/farmacología; Sitios de Unión; Simulación por Computador; Cristalografía por Rayos X; Diseño de Fármacos; Factor X/metabolismo; Pirrolidinonas/síntesis química; Pirrolidinonas/farmacología; Relación Estructura-Actividad

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirrolidinonas / Factor X / Anticoagulantes Tipo de estudio: Prognostic_studies Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2010 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido

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