Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Abstract

Regulation of tissue-specific glucocorticoid action by inhibiting 11b-HSD1 activity is regarded as a potential viable treatment for metabolic and cardiovascular diseases. Our effort to find an alternative to the highly favoured adamantyl moiety found in many potent 11b-HSD1 inhibitors led to the synthesis and SAR study of a series of phenyl ethanone thiadiazole derivatives. Potent compounds were identified with IC 50 values in the range 100-300 nM in biological evaluation on an HEK293 cell line stably transfected with the human HSD11B1 gene. These compounds are selective with no activity against human 11b-HSD2. An SAR study revealed the favoured combination of phenyl substitution and the linker system being meta-methoxy with a sulphide linker (18) or a para-trifluoromethyl with sulphoxide linker (27). Docking of 3 into a crystal structure of the enzyme shows how the substituted phenyl group of this new series might mimic the adamantane motif. Potent inhibitors 18 and 27 are new templates for further optimization.

Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

“…We have previous discovered that a substituted phenyl group may potentially be used as a replacement for the adamantyl group 33 . We therefore pursued the synthesis of a set of polycyclic or substituted aliphatic cyclic compounds in the carboxamide series Table 5.…”

Medicinal Chemistry of Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

“…Further optimization on this series led to thio-linked heterocycles such as triazole 133 that were more potent (IC 50 = 19 nM) . Work on alternatives to the adamantyl group led to aryl ketones exemplified by 134 which were less potent (IC 50 = 138 nM) . The authors note that the ketone series ( 131 – 134 ) have the potential to be substrates for the enzyme in a similar way to that reported by Wyeth but comment that they have not tested this hypothesis.…”

Synthesis and bioactivities of 1-(4-hydroxyphenyl)-2-((heteroaryl)thio)ethanones as carbonic anhydrase I, II and acetylcholinesterase inhibitors

“…2-Bromo-4'-hydroxyacetophenone was attached to the heterocyclic rings via thioether functional group by conducting a single step reaction. The compounds 1, 2, 3, 5, and 6 were found as registered compounds at the Sci Finder database without any article and experimental data, while compound 4 [42] was reported as an intermediate. Therefore, the current study is the first study for the synthesis and bioactivities of 1, 2, 3, 5, and 6.…”