Beneficial Hydroxyl Substitution
This paper from scientists at Bayer describes the discovery of two IRAK4 inhibitors. There are many aspects to the drug design but here we highlight the beneficial impact of hydroxyl substitution at two different parts of the structure.
Dual hydroxylation was found to improve both selectivity and the PK profile of these IRAK4 inhibitors. Introduction of a hydroxyl group to compound 30 resulted in an equally potent compound 31 but with “protection” from oxidative metabolism resulting in a more promising PK profile. In parallel, replacement of the methoxy group at the 6-position of the indazole moiety with a 2-hydroxy-propan-2-yl to form compound 33 also afforded some protection from oxidative metabolism. Although compound 33 was slightly less potent, it was found to have better selectivity, however still suffered from relatively high clearance.
Combining both hydroxyl substitutions in BAY1830839 (IRAK4= 3 nM, FLT3= 167 nM) resulted in a metabolically stable clinical candidate with high oral bioavailability, retaining high potency with high selectivity. A further clinical candidate was created by derivatising the 2-position through introduction of a sulfone moiety to make BAY1834845 (IRAK4= 8 nM, FLT3= 243 nM). Both compounds were reported to have advanced to clinical trials.
IRAK4: interleukin-1 receptor-associated kinase 4
FLT3: FMS-like tyrosine kinase 3
Paper
Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839
Ulrich Bothe, Judith Günther, Reinhard Nubbemeyer, Holger Siebeneicher, Sven Ring, Ulf Bömer, Michaele Peters, Alexandra Rausch, Karsten Denner, Herbert Himmel, Andreas Sutter, Ildiko Terebesi, Martin Lange, Antje M. Wengner, Nicolas Guimond, Tobias Thaler, Johannes Platzek, Uwe Eberspächer, Martina Schäfer, Holger Steuber, Thomas M. Zollner, Andreas Steinmeyer, and Nicole Schmidt.
Journal of Medicinal Chemistry 2024 67 (2), 1225-1242. https://doi.org/10.1021/acs.jmedchem.3c01714