Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 25, Issue 9, Pages 1836-1841Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.03.043
Keywords
Interleukin receptor-associated kinases; Inflammation; Drug discovery; SAR; Structure based drug design
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Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities. (C) 2015 Elsevier Ltd. All rights reserved.
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