First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis

B Laleu, F Gaggini, M Orchard… - Journal of medicinal …, 2010 - ACS Publications
B Laleu, F Gaggini, M Orchard, L Fioraso-Cartier, L Cagnon, S Houngninou-Molango…
Journal of medicinal chemistry, 2010ACS Publications
We describe the design, synthesis, and optimization of first-in-class series of inhibitors of
NADPH oxidase isoform 4 (Nox4), an enzyme implicated in several pathologies, in particular
idiopathic pulmonary fibrosis, a life-threatening and orphan disease. Initially, several
moderately potent pyrazolopyridine dione derivatives were found during a high-throughput
screening campaign. SAR investigation around the pyrazolopyridine dione core led to the
discovery of several double-digit nanomolar inhibitors in cell free assays of reactive oxygen …
We describe the design, synthesis, and optimization of first-in-class series of inhibitors of NADPH oxidase isoform 4 (Nox4), an enzyme implicated in several pathologies, in particular idiopathic pulmonary fibrosis, a life-threatening and orphan disease. Initially, several moderately potent pyrazolopyridine dione derivatives were found during a high-throughput screening campaign. SAR investigation around the pyrazolopyridine dione core led to the discovery of several double-digit nanomolar inhibitors in cell free assays of reactive oxygen species (ROS) production, showing high potency on Nox4 and Nox1. The compounds have little affinity for Nox2 isoform and are selective for Nox4/1 isoforms. The specificity of these compounds was confirmed in an extensive in vitro pharmacological profile, as well as in a counterscreening assay for potential ROS scavenging. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo, allowing further clinical trials for the potential treatment of fibrotic diseases, cancers, and cardiovascular and metabolic diseases.
ACS Publications