Patent Evaluation: Bridged Cyclic Ketal Derivatives as Squalene Synthetase Inhibitors

Summary

Novelty: Bridged cyclic ketals are described which are claimed to inhibit squalene synthase, thereby having potential in the treatment of fungal diseases, hypercholesterolaemia and hyperlipoproteinaemia.

Biology: Squalene synthase inhibitory activity was determined by incubation of the compound with [2-¹⁴C]-farnesylpyrophosphate and homogenized rat liver, and measurement of the concentration of [¹⁴C] squalene produced. IC₅₀ (50% inhibition) values were < 100 nM for forty-four compounds. In vitro activity against Candida albicans was also included.

Chemistry: Several cyclic ketals, obtained by fermentation, were chemically modified to produce novel derivatives. Over sixty intermediates and sixty-eight compounds are fully exemplified. Over twenty compounds are specifically claimed, including [1S-[1α(4S*,5S*),3α,4β,5α,6α(2E,4R*,6R*)7β]] 1-(4-hydroxy-5-methyl-3-methylene-6-phenylhexyl)- 4,6,7-trihydxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid-6-(4,6-dimethyl-2-octenoate).

Structure: