Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Metabolic Stability

  • J Med Chem. 2016 Oct 13;59(19):9228-9242. doi: 10.1021/acs.jmedchem.6b01169.
Leena Patel  1 ,  Jayaraman Chandrasekhar  1 ,  Jerry Evarts  1 ,  Kristen Forseth  1 ,  Aaron C Haran  1 ,  Carmen Ip  1 ,  Adam Kashishian  1 ,  Musong Kim  1 ,  David Koditek  1 ,  Sandy Koppenol  1 ,  Latesh Lad  1 ,  Eve-Irene Lepist  1 ,  Mary E McGrath  1 ,  Stephane Perreault  1 ,  Kamal D Puri  1 ,  Armando G Villaseñor  1 ,  John R Somoza  1 ,  Bart H Steiner  1 ,  Joseph Therrien  1 ,  Jennifer Treiberg  1 ,  Gary Phillips  1
Affiliations
  • 1. Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 27660855 DOI: 10.1021/acs.jmedchem.6b01169
Abstract

Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and Rheumatoid Arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of Rheumatoid Arthritis.

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