RESUMEN
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Asunto(s)
Ácidos Carboxílicos/química , Descubrimiento de Drogas , Factor VIIa/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Benzamidinas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factor VIIa/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Relación Estructura-ActividadRESUMEN
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Asunto(s)
Descubrimiento de Drogas , Glicina/análogos & derivados , Oxazoles/química , Oxazoles/farmacología , PPAR alfa/agonistas , Animales , Línea Celular , Cricetinae , Cristalografía por Rayos X , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Glicina/toxicidad , Humanos , Masculino , Ratones , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/toxicidad , PPAR alfa/química , PPAR alfa/genética , Estructura Terciaria de Proteína , Especificidad por Sustrato , Activación Transcripcional/efectos de los fármacosRESUMEN
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.