Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors

Pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives are new chemical entities with good and attractive druglikeness properties. A series of pyrazolo-pyrido-diazepine dione analogs demonstrated to be particularly amenable to lead optimization through a couple of cycles in order to imp...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-12, Vol.19 (23), p.6989-6999
Main Authors: Gaggini, Francesca, Laleu, Benoît, Orchard, Mike, Fioraso-Cartier, Laetitia, Cagnon, Laurène, Houngninou-Molango, Sophie, Gradia, Angelo, Duboux, Guillaume, Merlot, Cédric, Heitz, Freddy, Szyndralewiez, Cédric, Page, Patrick
Format: Article
Language:English
Subjects:
Administration, Oral
animal models
Animals
Antifibrotic
Azepines - chemical synthesis
Azepines - chemistry
Azepines - pharmacology
bioactive properties
Biological and medical sciences
Bleomycin - toxicity
chemistry
Disease Models, Animal
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
fibroblasts
fibrosis
Humans
in vitro studies
Inhibitor
IPF
Male
Medical sciences
Mice
Mice, Inbred C57BL
NADPH oxidase
NADPH Oxidase 1
NADPH Oxidase 4
NADPH Oxidases - antagonists & inhibitors
Nox1
Nox4
Oxazines - chemical synthesis
Oxazines - chemistry
Oxazines - pharmacology
pharmacokinetics
Pharmacology. Drug treatments
Pirfenidone
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - drug therapy
Pyrazines - chemical synthesis
Pyrazines - chemistry
Pyrazines - pharmacology
Pyrazolo-pyrido-dione
Pyridones - pharmacology
Respiratory system
Structure-Activity Relationship
therapeutics
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Description
Summary:Pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives are new chemical entities with good and attractive druglikeness properties. A series of pyrazolo-pyrido-diazepine dione analogs demonstrated to be particularly amenable to lead optimization through a couple of cycles in order to improve specificity for isoforms Nox4 and Nox1 and had excellent pharmacokinetic parameters by oral route. Several molecules such as compound 7c proved to be highly potent in in vitro assays on human lung fibroblasts differentiation as well as in curative murine models of bleomycin-induced pulmonary fibrosis with superior efficiency over Pirfenidone. Pyrazolo-pyrido-diazepine dione derivatives targeting Nox4 and Nox1 isoforms appear highly promising therapeutics for the treatment of idiopathic pulmonary fibrosis.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.10.016