131666-74-5Relevant articles and documents
Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases
Allart, Brigitte,Auberval, Marielle,Blanc, Javier,Borgonovi, Monica,Brys, Reginald,Bucher, Denis,Christophe, Thierry,Coornaert, Beatrice,De Wachter, Maxim,Duys, Inge,El Bkassiny, Sandy,Heckmann, Bertrand,Houvenaghel, Nicolas,Jagerschmidt, Catherine,Jans, Mia,Jansen, Koen,Jaunet, Alex,Lecru, Lola,Letfus, Vatroslav,Mammoliti, Oscar,Marsais, Florence,Menet, Christel,Oste, Line,Palisse, Adeline,Poljak, Tanja,Pujuguet, Philippe,Rupcic, Renata,Saniere, Laurent,Smehil, Mario,Sonck, Kathleen,Triballeau, Nicolas,Tricarico, Giovanni,Waeckel, Ludovic,Wakselman, Emanuelle
supporting information, p. 14557 - 14586 (2021/10/20)
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.
INDOMETHACIN ANALOGS FOR THE TREATMENT OF CASTRATE-RESISTANT PROSTATE CANCER
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Page/Page column 64, (2013/05/09)
Provided are compositions for inhibiting a biological activity of an aldoketo reductase family 1, member C3 (AKR1 C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1 C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.
Straightforward protocol for the efficient synthesis of varied N 1-acylated (aza)indole 2-/3-alkanoic acids and esters: Optimization and scale-up
Liedtke, Andy J.,Kim, Kwangho,Stec, Donald F.,Sulikowski, Gary A.,Marnett, Lawrence J.
supporting information, p. 10049 - 10058 (2013/01/14)
A library of approximately 40 N1-acylated (aza)indole alkanoic esters and acids was prepared employing a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of the indole substitution pattern, and high overall yield. Additionally, the procedure has been scaled up to yield multi-gram amounts of preferred indole compounds, e.g.: 2′-des-methyl indomethacin 2. The reported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo studies at relevant molecular targets.
