Molecular mechanisms underlying the antiatherosclerotic and antidiabetic effects of probucol, succinobucol, and other probucol analogues.

New therapies for the management of cardiovascular disease remain highly desirable, yet the recently developed agents, such as the cholesterylester transfer protein inhibitor torcetrapib, the antidiabetic agent rosiglitazone, and anti-inflammatory inhibitors of cyclooxygenase-2, have failed. In this review, the more recent developments in the molecular mechanisms underlying the beneficial activities of probucol and related compounds are described. In-vivo and in-vitro studies have revealed that several of the protective activities of probucol can be explained by the ability of this drug to induce the enzyme heme oxygenase-1. It is now apparent that the sulfur atoms, rather than the phenol moieties of probucol, are required for its antiatherogenic and antirestenotic activities. Compounds related to probucol that have improved efficacy without the adverse effects offer promise as novel therapies of cardiovascular disease. Recent results suggest these compounds may also be used for the prevention of type-2 diabetes, a disease that is increasing in prevalence and importance worldwide. The development of derivatives of probucol targeting anti-inflammatory and antioxidant processes, perhaps via induction of heme oxygenase-1, may add to the armamentarium of current agents used in treatment of atherosclerotic disease and diabetes.