Design and biological evaluation of a series of thiophene-based 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

A series of highly functionalized thiophene-based 3,5-dihydroxyheptenoic acid derivatives (10) were prepared from aldehydes 6 by homologation, aldol condensation with ethyl acetoacetate dianion and stereoselective β-hydroxyketone reduction. High levels of HMG-CoA reductase inhibitory activity have been found within the series. The most active analog in vitro was 10i whereas in vivo, 10e, 10i, 10m, 10n, 10o, and 10v were approximately equipotent.