Discovery of 5-Amino- N -(1 H -pyrazol-4-yl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide Inhibitors of IRAK4

Journal Article · Thu Jun 11 04:00:00 EDT 2015 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.5b00107· OSTI ID:1404964

Lim, Jongwon; Altman, Michael D.; Baker, James; Brubaker, Jason D.; Chen, Hongmin; Chen, Yiping; Fischmann, Thierry; Gibeau, Craig; Kleinschek, Melanie A.; Leccese, Erica; Lesburg, Charles; Maclean, John K. F.; Moy, Lily Y.; Mulrooney, Erin F.; Presland, Jeremy; Rakhilina, Larissa; Smith, Graham F.; Steinhuebel, Dietrich; Yang, Ruojing

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1404964
• Journal Information: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 6 Vol. 6; ISSN 1948-5875
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES