title: Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4.
abstract: 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.
authors: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States. Electronic address: william.mcelroy@merck.com.
authors: William T
authors: WT
authors: McElroy
authors: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: W
authors: W
authors: Michael Seganish
authors: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors: R
authors: R
authors: Jason Herr
authors: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors: James
authors: J
authors: Harding
authors: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors: Jinhai
authors: J
authors: Yang
authors: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors: Larry
authors: L
authors: Yet
authors: Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore.
authors: Venukrishnan
authors: V
authors: Komanduri
authors: Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore.
authors: Koraboina Chandra
authors: KC
authors: Prakash
authors: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: Brian
authors: B
authors: Lavey
authors: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: Deen
authors: D
authors: Tulshian
authors: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: William J
authors: WJ
authors: Greenlee
authors: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: Christopher
authors: C
authors: Sondey
authors: Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: Thierry O
authors: TO
authors: Fischmann
authors: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors: Xiaoda
authors: X
authors: Niu
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000604975:2,6-diaminopyrimidine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Drug discovery; Inflammation; Interleukin receptor-associated kinases; SAR; Structure based drug design