Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
- J Med Chem. 2017 Jun 22;60(12):5193-5208. doi: 10.1021/acs.jmedchem.7b00618.
- 1. Research & Development, Bristol-Myers Squibb Company , Route 206 and Province Line Road, Princeton, New Jersey 08543, United States.
- 2. Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
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.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: PI3KResearch Areas: Inflammation/Immunology
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Research Areas: Inflammation/Immunology