Abstract
Objective: Gene deficient or knockout (KO) mice and rabbits are models of atherosclerosis focusing on cholesterol plaques, which do not reflect the complex etiology of cardiovascular disease (CVD). One-drug-one-target, paradigm has produced the statins but are at best palliative. CVD is of a multiple etiology and this study aims to develop a combo-compound therapy complementing the multifactorial nature of the disease.
Methods and results: A conceptual thromboembolic pathway were constructed to reflect the multiple etiology of CVD. Druggable sites were identified and new chemical entities (NCEs) synthesized to match target sites, then a series of 3-NCE combos were designed to address in toto the thromboembolic pathway. A natural mouse was created to produce plaques and plaque reduction was the end point to evaluate the curative and/or preventive treatment effect of the 3-NCE combos. Histopathology monitored the presence of plaque, but a 4-panel biomarker, based on glycocalyx disruption, was subsequently developed as a surrogate to monitor plaque formation. Of the 12 different 3-NCE combos, four were found to be both curative and preventive. One combo was chosen and given the designation Embotricin™.
Conclusions: CVD and its multiple etiology is preventable and curable adapting a combo-drug therapeutic platform.