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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