title: Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors.
abstract: 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.
authors: Genkyotex S.A., 16 Chemin des Aulx, CH-1228 Plan-Les-Ouates, Switzerland.
authors: Francesca
authors: F
authors: Gaggini
authors: Benoît
authors: B
authors: Laleu
authors: Mike
authors: M
authors: Orchard
authors: Laetitia
authors: L
authors: Fioraso-Cartier
authors: Laurène
authors: L
authors: Cagnon
authors: Sophie
authors: S
authors: Houngninou-Molango
authors: Angelo
authors: A
authors: Gradia
authors: Guillaume
authors: G
authors: Duboux
authors: Cédric
authors: C
authors: Merlot
authors: Freddy
authors: F
authors: Heitz
authors: Cédric
authors: C
authors: Szyndralewiez
authors: Patrick
authors: P
authors: Page
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D010078:Oxazines; D011719:Pyrazines; D011728:Pyridones; D001761:Bleomycin; C093844:pirfenidone; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human