title: Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation.
abstract: IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: William T
authors.initials: WT
authors.lastname: McElroy
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ginny
authors.initials: G
authors.lastname: Ho
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sunil
authors.initials: S
authors.lastname: Paliwal
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Li
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Seganish
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Tata
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sondey
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Bian
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Loretta
authors.initials: L
authors.lastname: Bober
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Devito
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.affiliation: Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Niu
keywords: Interleukin-1 receptor-associated kinase 4; SAR; drug discovery; inflammation; structure-based drug design