27545-57-9Relevant articles and documents
Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease
Emmerich, Juliette,Van Koppen, Chris J.,Burkhart, Jens L.,Hu, Qingzhong,Siebenbürger, Lorenz,Boerger, Carsten,Scheuer, Claudia,Laschke, Matthias W.,Menger, Michael D.,Hartmann, Rolf W.
supporting information, p. 5086 - 5098 (2017/06/28)
Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3-phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 μM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study.
Microwave-assisted generation and reactions of nitrile sulfides
Morrison, Angus J.,Paton, R. Michael,Sharp, Robert D.
, p. 807 - 813 (2007/10/03)
An improved practical method is described for the generation of benzonitrile sulfide based on microwave-assisted decarboxylation of 5-phenyl-1,3,4-oxathiazol-2-one. Reaction times for the preparation of cycloadducts (e.g. isothiazoles and 1,2,4-thiadiazoles) derived from the nitrile sulphide are reduced from typically 15-30 h to approximately 15 min.
