RESUMEN
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Ácidos Hidroxámicos/farmacología , Inhibidores de Proteasas/farmacología , Proteína ADAM17 , Animales , Área Bajo la Curva , Disponibilidad Biológica , Descubrimiento de Drogas , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacocinética , Modelos Moleculares , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Asunto(s)
Química Farmacéutica/métodos , Receptor Cannabinoide CB2/química , Sulfonas/química , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cinética , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Receptores de Droga , Sodio/química , Relación Estructura-ActividadRESUMEN
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.
Asunto(s)
Receptor Cannabinoide CB2/metabolismo , Sulfonas/metabolismo , Ligandos , Receptor Cannabinoide CB2/antagonistas & inhibidores , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
A thorough SAR study of the oxime region of the dual NK(1)/NK(2) antagonist 1 revealed several modifications that result in potent dual antagonists. Follow up SAR studies on a second-generation scaffold demonstrate that certain polar groups on the oxime can improve the dual binding affinity to the subnanomolar range.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Oximas/síntesis química , Oximas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Animales , Área Bajo la Curva , Cobayas , Estructura Molecular , Oximas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benzimidazolinone series of compounds which display single digit nanomolar NK(1)/NK(2) affinity and near micromolar binding for the NK(3) receptor.