RESUMEN
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
Asunto(s)
Antineoplásicos/química , Isoindoles/química , Piperidinas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoindoles/administración & dosificación , Isoindoles/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temozolomida , Neoplasias de la Mama Triple NegativasRESUMEN
We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.