title: Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4.
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.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States. Electronic address: william.seganish@merck.com.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Seganish
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: William T
authors.initials: WT
authors.lastname: McElroy
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brumfield
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors.forename: James
authors.initials: J
authors.lastname: Harding
authors.affiliation: Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore.
authors.forename: Venukrishnan
authors.initials: V
authors.lastname: Komanduri
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Julius
authors.initials: J
authors.lastname: Matasi
authors.affiliation: Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park III, Singapore 117525, Singapore.
authors.forename: Koraboina Chandra
authors.initials: KC
authors.lastname: Prakash
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Yang
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, United States.
authors.forename: Larry
authors.initials: L
authors.lastname: Yet
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Devito
authors.affiliation: Respiratory and Immunology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Respiratory and Immunology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Niu
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sondey
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011743:Pyrimidines; D051197:Toll-Like Receptor 4; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Aminopyrimidine; IRAK4; Inflammation; Kinase; Structure activity relationships