| Literature DB >> 28541707 |
Qingjie Liu1, Qing Shi1, David Marcoux1, Douglas G Batt1, Lyndon Cornelius1, Lan-Ying Qin1, Zheming Ruan1, James Neels1, Myra Beaudoin-Bertrand1, Anurag S Srivastava1, Ling Li1, Robert J Cherney1, Hua Gong1, Scott H Watterson1, Carolyn Weigelt1, Kathleen M Gillooly1, Kim W McIntyre1, Jenny H Xie1, Mary T Obermeier1, Aberra Fura1, Bogdan Sleczka1, Kevin Stefanski1, R M Fancher1, Shweta Padmanabhan2, Thatipamula Rp2, Ipsit Kundu2, Kallem Rajareddy, Rodney Smith1, James K Hennan1, Dezhi Xing1, Jingsong Fan1, Paul C Levesque1, Qian Ruan1, Sidney Pitt1, Rosemary Zhang1, Donna Pedicord1, Jie Pan1, Melissa Yarde1, Hao Lu1, Jonathan Lippy1, Christine Goldstine1, Stacey Skala1, Richard A Rampulla1, Arvind Mathur1, Anuradha Gupta2, Pirama Nayagam Arunachalam2, John S Sack1, Jodi K Muckelbauer1, Mary Ellen Cvijic1, Luisa M Salter-Cid1, Rajeev S Bhide2, Michael A Poss1, John Hynes1, Percy H Carter1, John E Macor, Stefan Ruepp1, Gary L Schieven1, Joseph A Tino1.
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.Entities:
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Year: 2017 PMID： 28541707 DOI： 10.1021/acs.jmedchem.7b00618
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446