title: Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications.
abstract: IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States. Electronic address: jongwon_lim@merck.com.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Chemistry Modeling and Informatics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Brubaker
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Kleinschek
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Chaomin
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Duan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Chemistry Modeling and Informatics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: John K F
authors.initials: JK
authors.lastname: Maclean
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Mulrooney
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Presland
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Larissa
authors.initials: L
authors.lastname: Rakhilina
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Graham F
authors.initials: GF
authors.lastname: Smith
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Ruojing
authors.initials: R
authors.lastname: Yang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D011720:Pyrazoles; C031280:pyrazole; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IRAK4; Kinase inhibitor; N-(1H-Pyrazol-4-yl)carboxamide; SAR; Serine–threonine kinase