RESUMEN
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.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Bencimidazoles/síntesis química , Hipoglucemiantes/síntesis química , Indazoles/síntesis química , Indoles/síntesis química , Pirazoles/síntesis química , Compuestos de Espiro/síntesis química , Animales , Bencimidazoles/química , Diseño de Fármacos , Humanos , Hipoglucemiantes/química , Indazoles/química , Indoles/química , Isoenzimas/antagonistas & inhibidores , Hígado/enzimología , Músculo Esquelético/enzimología , Pirazoles/química , Relación Estructura-Actividad Cuantitativa , Ratas , Compuestos de Espiro/químicaRESUMEN
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.