title: Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors.
abstract: IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States. Electronic address: jennifer.hanisak@merck.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hanisak
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Seganish
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: William T
authors.initials: WT
authors.lastname: McElroy
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: Haiquin
authors.initials: H
authors.lastname: Tang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: Hon-Chung
authors.initials: HC
authors.lastname: Tsui
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: Theirry
authors.initials: T
authors.lastname: Fischmann
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States.
authors.forename: James
authors.initials: J
authors.lastname: Tata
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
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
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006207:Half-Life; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IRAK4; Inflammation; Interleukin receptor-associated kinases; SAR; Toll-like receptors