| Literature DB >> 26101574 |
Jongwon Lim1, Michael D Altman1, James Baker1, Jason D Brubaker1, Hongmin Chen1, Yiping Chen1, Thierry Fischmann1, Craig Gibeau1, Melanie A Kleinschek1, Erica Leccese1, Charles Lesburg1, John K F Maclean1, Lily Y Moy1, Erin F Mulrooney1, Jeremy Presland1, Larissa Rakhilina1, Graham F Smith1, Dietrich Steinhuebel1, Ruojing Yang1.
Abstract
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.Entities:
Keywords: 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; IRAK4; SAR; inflammatory disease; kinase inhibitor; serine-threonine kinase
Year: 2015 PMID： 26101574 PMCID： PMC4468400 DOI： 10.1021/acsmedchemlett.5b00107
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345