RESUMEN
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Modelos Moleculares , Ratas , Bibliotecas de Moléculas Pequeñas/farmacocinética , Relación Estructura-ActividadRESUMEN
The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacología , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Iminas/química , Osteoporosis/tratamiento farmacológico , Técnicas de Placa-Clamp , Fenetilaminas , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonamidas , Sulfonas/químicaRESUMEN
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.