The Design of Multi-target Drugs to Treat Cardiovascular Diseases: Two (or more) Birds on One Stone

Cardiovascular diseases (CVDs) comprise a group of diseases and disorders of the heart and blood vessels, which together are the number one cause of death worldwide, being associated with multiple genetic and modifiable risk factors, and that may directly arise from different etiologies. For a long time, the search for cardiovascular drugs was based on the old paradigm "one compound - one target", aiming to obtain a highly potent and selective molecule with only one desired molecular target. Although historically successful in the last decades, this approach ignores the multiple causes and the multifactorial nature of CVDs. Thus, over time, treatment strategies for cardiovascular diseases have changed, and, currently, pharmacological therapies for CVD are mainly based on the association of two or more drugs to control symptoms and reduce cardiovascular death. In this context, the development of multitarget drugs, i.e., compounds having the ability to act simultaneously at multiple sites, is an attractive and relevant strategy that can be even more advantageous to achieve predictable pharmacokinetic and pharmacodynamics correlations as well as better patient compliance. In this review, we aim to highlight the efforts and rational pharmacological bases for the design of some promising multitargeted compounds to treat important cardiovascular diseases like heart failure, atherosclerosis, acute myocardial infarction, pulmonary arterial hypertension, and arrhythmia.