The Wonders of Phosphodiesterase-5 Inhibitors: A Majestic History

Abstract

The Nobel Prize winning discovery of nitric oxide (NO) in 1986 was the starting point for a new innovation in drug discovery. NO acting as a mediator at different physiological systems is believed to be involved in many physiological and pathological conditions through the formation of the second messenger cyclic guanosine monophosphate (cGMP). cGMP-dependent vasodilation effect of NO is important in regulating pulmonary and systemic pressures, maintaining penis erection, preventing atherosclerosis, preventing platelet aggregation, and protecting and controlling cardiac functions. The main enzyme involved in the termination of cGMP effects is phosphodiesterase enzyme 5 (PDE-5), which is overexpressed in ventricular hypertrophy and heart failure. A milestone in drug discovery was the selective inhibitors of PDE-5 that developed to be a multibillion dollar blockbuster in drug market. PDE-5 inhibitors are approved for the treatment of erectile dysfunctions (EDs), pulmonary hypertension, and benign prostatic hypertrophy. They are also under clinical trials for their cardiac protection against damage induced by ischemia or heart failure. This review article is an update about the pharmacotherapeutics of PDE-5 inhibitors and the majestic history that led to their discovery. The information reported in this review was obtained from the electronic sources of different databases such as PubMed Central, Google Scholar, and Scopus. Keywords used for search included cGMP (mechanisms and functions), EDs (drugs used), nitric oxide, and PDE-5 inhibitors (clinical applications). A total of 165 articles were studied, of which 45 articles were referred to in this review.

Keywords: Cyclic guanosine monophosphate; Nitric oxide; Phosphodiesterase enzyme 5 inhibitors.

Figure 1

(a) In the endothelial cell, nitric oxide is produced from L-arginine by the enzymatic action of nitric oxide synthase. (b) In the cell, nitric oxide will activate soluble guanylyl cyclase converting guanosine triphosphate to cyclic guanosine monophosphate. Cyclic guanosine monophosphate will activate cyclic guanosine monophosphate-dependent protein kinase, which leads to a decrease in intracellular calcium (Ca++)^I (see text for details). The actions of cyclic guanosine monophosphate are terminated by hydrolysis by phosphodiesterase enzyme 5