27545-57-9Relevant academic research and scientific papers
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-induced generation and reactions of nitrile sulfides: An improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles
Fordyce, Euan A.F.,Morrison, Angus J.,Sharp, Robert D.,Paton, R. Michael
experimental part, p. 7192 - 7197 (2010/10/01)
The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation of 1,3,4-oxathiazol-2-ones, have been investigated. By this approach ethyl 1,2,4-thiadiazole-5-carboxylates 3 were prepared in good yield by cycloaddition of the nitrile sulfides to ethyl cyanoformate. Similarly, reaction of benzonitrile sulfide with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 3-phenylisothiazole-4,5- dicarboxylate (5). In contrast, o-hydroxybenzonitrile sulfide, generated from the corresponding oxathiazolone 2d, reacted with DMAD to give methyl 4-oxo-4H-[1]benzopyrano[4,3-c]isothiazole-3-carboxylate (8) in high yield. A ca. 1:1 mixture of ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7) was formed from benzonitrile sulfide and ethyl propiolate. The corresponding reaction with diethyl fumarate gave diethyl trans-4,5-dihydro-3-phenylisothiazole-4,5- dicarboylate (10). 3-Arylisothiazoles, unsubstituted at both the 4- and 5-positions, were prepared from the reaction of 5-aryl-1,3,4-oxathiazolones with norbornadiene by a pathway involving cycloaddition of the nitrile sulfide to the norbornadiene, followed by retro-Diels-Alder extrusion of cyclopentadiene from the resulting isothiazoline cycloadduct 12. In summary, the use of microwave irradiation, rather than conventional heating methods, allows nitrile sulfide generation and reactions to be carried out in shorter times, with easier work-up and, in some cases, in higher yields.
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.
