1,2-Dibenzamidobenzene inhibitors of human factor Xa.

Herron, D K; Goodson, T; Wiley, M R; Weir, L C; Kyle, J A; Yee, Y K; Tebbe, A L; Tinsley, J M; Mendel, D; Masters, J J; Franciskovich, J B; Sawyer, J S; Beight, D W; Ratz, A M; Milot, G; Hall, S E; Klimkowski, V J; Wikel, J H; Eastwood, B J; Towner, R D; Gifford-Moore, D S; Craft, T J; Smith, G F

Herron, D K; Goodson, T; Wiley, M R; Weir, L C; Kyle, J A; Yee, Y K; Tebbe, A L; Tinsley, J M; Mendel, D; Masters, J J; Franciskovich, J B; Sawyer, J S; Beight, D W; Ratz, A M; Milot, G; Hall, S E; Klimkowski, V J; Wikel, J H; Eastwood, B J; Towner, R D; Gifford-Moore, D S; Craft, T J; Smith, G F.

Afiliación

Herron DK; Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA. dkherron@lilly.com

J Med Chem ; 43(5): 859-72, 2000 Mar 09.

Article en En | MEDLINE | ID: mdl-10715153

RESUMEN

High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K(ass) = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K(ass) = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.

Asunto(s)

Anticoagulantes/síntesis química; Inhibidores Enzimáticos/síntesis química; Inhibidores del Factor Xa; Fenilendiaminas/síntesis química; Sulfonamidas/síntesis química; Trombina/antagonistas & inhibidores; Anticoagulantes/química; Anticoagulantes/metabolismo; Sitios de Unión; Inhibidores Enzimáticos/química; Inhibidores Enzimáticos/metabolismo; Factor Xa/química; Factor Xa/metabolismo; Humanos; Modelos Moleculares; Fenilendiaminas/química; Fenilendiaminas/metabolismo; Fenilendiaminas/farmacología; Inhibidores de Serina Proteinasa/síntesis química; Inhibidores de Serina Proteinasa/química; Inhibidores de Serina Proteinasa/metabolismo; Relación Estructura-Actividad; Sulfonamidas/química; Sulfonamidas/metabolismo; Sulfonamidas/farmacología; Trombina/metabolismo

Buscar en Google

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenilendiaminas / Sulfonamidas / Trombina / Inhibidores Enzimáticos / Inhibidores del Factor Xa / Anticoagulantes Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Buscar en Google

Añadir a Mi BVS

Imprimir

XML

PubMed Links