| Literature DB >> 26980109 |
Leena Patel1,2, Jayaraman Chandrasekhar1,2, Jerry Evarts1,2, Aaron C Haran1,2, Carmen Ip1,2, Joshua A Kaplan1,2, Musong Kim1,2, David Koditek1,2, Latesh Lad1,2, Eve-Irene Lepist1,2, Mary E McGrath1,2, Nikolai Novikov1,2, Stephane Perreault1,2, Kamal D Puri1,2, John R Somoza1,2, Bart H Steiner1,2, Kirk L Stevens1,2, Joseph Therrien1,2, Jennifer Treiberg1,2, Armando G Villaseñor1,2, Arthur Yeung1,2, Gary Phillips1,2.
Abstract
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.Entities:
Mesh：
Substances：
Year: 2016 PMID： 26980109 DOI： 10.1021/acs.jmedchem.6b00213
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446