First in Class, Potent, and Orally Bioavailable NADPH Oxidase Isoform 4 (Nox4) Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis
Abstract
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.
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BH4 can be oxidized in vivo by molecular oxygen or ROS to generate dihydrobiopterin (BH2), a pterin unable to support NO synthesis.
“BH4 can be oxidized in vivo by molecular oxygen or ROS to generate dihydrobiopterin (BH2), a pterin very structurally similar to BH4 but unable to support NO synthesis (544, 753, 933).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [544]
GKT136901 and GKT137831 were identified by Laleul and colleagues during a screen for Nox4 inhibitors.
“GKT136901 and GKT137831 were identified by Laleul and colleagues during a screen for Nox4 inhibitors [405].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [405]
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- Authors
- Laleu, B., Gaggini, F., Orchard, M., Fioraso-Cartier, L., Cagnon, L., Houngninou-Molango, S., Gradia, A., Duboux, G., Merlot, C., Heitz, F., Szyndralewiez, C., & Page, P.
- Affiliations
- Genkyotex (Switzerland) (CH)
- Corresponding author
- Page, Patrick
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-10-13
- Volume
- 53
- Issue
- 21
- Pages
- 7715-7730
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2005662241
- Cited by
- 243
- References
- 50
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 13 · 2022: 11 · 2021: 12 · 2020: 21 · 2019: 12 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 22 · 2014: 22 · 2013: 27 · 2012: 27
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- idiopathic pulmonary fibrosis, reactive oxygen species, enzyme selectivity, NOX1, NOX2, oral bioavailability, structure-activity relationship, high-throughput screening, fibrotic diseases
- MeSH terms
- NADPH Oxidase 4, Administration, Oral, Animals, Biological Availability, Cell Line, Chronic Disease, Cricetulus, Cricetinae, Humans, Isoenzymes, Kidney Diseases, Male, Microsomes, Liver, Pulmonary Fibrosis, Pyrazoles, Pyridines, Structure-Activity Relationship, Free Radical Scavengers, Rats, Sprague-Dawley, Reactive Oxygen Species, NADPH Oxidases, Rats, High-Throughput Screening Assays
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