Novel BET bromodomain inhibitors for cardiovascular and inflammatory disease

Cardiovascular diseases are still the major cause of morbidity and mortality in developed countries, and are strongly on the increase in developing countries. Major cause of cardiovascular diseases is atherosclerosis in the arteries supplying blood to heart, brain and legs. BET bromodomain proteins are key players in epigenetic regulation of gene expression,and are emerging as promising drug targets for multiple indications. Dybly is working on small molecules able to potently upregulate hepatic apoA-I production, increasing reverse cholesterol and so able to reduce atherosclerotic plaque burden. Our molecules recently emanated to be selective BET bromodomain inhibitors. We then started a medchem effort to obtain more potent derivatives, and succeeded in gaining a 100-fold increase in potency in apoA-I upregulation. Their broader anti-inflammatory potential was demonstrated by promising reductions of IL-6 release by cultured macrophages and reduction of tissue swelling after LPS administration in vivo. This opens the opportunity to develop these compounds for diseases like rheumatoid arthritis, inflammatory bowel diseases, asthma, or atopic dermatitis.