RESUMEN
Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.
Asunto(s)
Antivirales/química , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Sulfonamidas/química , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Benzazepinas/química , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies.
Asunto(s)
Fármacos Anti-VIH/química , Compuestos Aza/química , VIH-1/metabolismo , Indoles/química , Administración Oral , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , Semivida , Humanos , Piperazinas/química , Piperazinas/farmacocinética , Ácido Pirúvico , Ratas , Relación Estructura-Actividad , Acoplamiento Viral/efectos de los fármacosRESUMEN
A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7.