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ACS Med Chem Lett. 2015 May 12;6(6):677-82. doi: 10.1021/acsmedchemlett.5b00106. eCollection 2015 Jun 11.

Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation.

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1
Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

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.

KEYWORDS:

Interleukin-1 receptor-associated kinase 4; SAR; drug discovery; inflammation; structure-based drug design

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