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.
Qingjie Liu  1 ,  Qing Shi  1 ,  David Marcoux  1 ,  Douglas G Batt  1 ,  Lyndon Cornelius  1 ,  Lan-Ying Qin  1 ,  Zheming Ruan  1 ,  James Neels  1 ,  Myra Beaudoin-Bertrand  1 ,  Anurag S Srivastava  1 ,  Ling Li  1 ,  Robert J Cherney  1 ,  Hua Gong  1 ,  Scott H Watterson  1 ,  Carolyn Weigelt  1 ,  Kathleen M Gillooly  1 ,  Kim W McIntyre  1 ,  Jenny H Xie  1 ,  Mary T Obermeier  1 ,  Aberra Fura  1 ,  Bogdan Sleczka  1 ,  Kevin Stefanski  1 ,  R M Fancher  1 ,  Shweta Padmanabhan  2 ,  Thatipamula Rp  2 ,  Ipsit Kundu  2 ,  Kallem Rajareddy ,  Rodney Smith  1 ,  James K Hennan  1 ,  Dezhi Xing  1 ,  Jingsong Fan  1 ,  Paul C Levesque  1 ,  Qian Ruan  1 ,  Sidney Pitt  1 ,  Rosemary Zhang  1 ,  Donna Pedicord  1 ,  Jie Pan  1 ,  Melissa Yarde  1 ,  Hao Lu  1 ,  Jonathan Lippy  1 ,  Christine Goldstine  1 ,  Stacey Skala  1 ,  Richard A Rampulla  1 ,  Arvind Mathur  1 ,  Anuradha Gupta  2 ,  Pirama Nayagam Arunachalam  2 ,  John S Sack  1 ,  Jodi K Muckelbauer  1 ,  Mary Ellen Cvijic  1 ,  Luisa M Salter-Cid  1 ,  Rajeev S Bhide  2 ,  Michael A Poss  1 ,  John Hynes  1 ,  Percy H Carter  1 ,  John E Macor ,  Stefan Ruepp  1 ,  Gary L Schieven  1 ,  Joseph A Tino  1
Affiliations
  • 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.
Abstract

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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