Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4.
Basic Information
ID: ALA3600286
Journal: Bioorg Med Chem Lett
Title: Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4.
Authors: Seganish WM, McElroy WT, Herr RJ, Brumfield S, Greenlee WJ, Harding J, Komanduri V, Matasi J, Prakash KC, Tulshian D, Yang J, Yet L, Devito K, Fossetta J, Garlisi CG, Lundell D, Niu X, Sondey C.
Abstract: IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.
CiteXplore: 26115573
DOI: 10.1016/j.bmcl.2015.05.097
Patent ID: ┄