1 research outputs found
Discovery of 5‑Amino‑<i>N</i>‑(1<i>H</i>‑pyrazol-4-yl)pyrazolo[1,5‑<i>a</i>]pyrimidine-3-carboxamide Inhibitors of IRAK4
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-<i>N</i>-(1<i>H</i>-pyrazol-4-yl)ÂpyrazoloÂ[1,5-<i>a</i>]Âpyrimidine-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