Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.
Qingjie LiuQing ShiDavid MarcouxDouglas G BattLyndon CorneliusLan-Ying QinZheming RuanJames NeelsMyra Beaudoin-BertrandAnurag S SrivastavaLing LiRobert J CherneyHua GongScott H WattersonCarolyn WeigeltKathleen M GilloolyKim W McIntyreJenny H XieMary T ObermeierAberra FuraBogdan SleczkaKevin StefanskiR M FancherShweta PadmanabhanThatipamula RpIpsit KunduKallem RajareddyRodney SmithJames K HennanDezhi XingJingsong FanPaul C LevesqueQian RuanSidney PittRosemary ZhangDonna PedicordJie PanMelissa YardeHao LuJonathan LippyChristine GoldstineStacey SkalaRichard A RampullaArvind MathurAnuradha GuptaPirama Nayagam ArunachalamJohn S SackJodi K MuckelbauerMary Ellen CvijicLuisa M Salter-CidRajeev S BhideMichael A PossJohn HynesPercy H CarterJohn E MacorStefan RueppGary L SchievenJoseph A TinoPublished in: Journal of medicinal chemistry (2017)
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.