1. Academic Validation
  2. Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

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

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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