Research Projects

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetics, with a 2-5 times higher risk than other cardiac risk factors. Current treatments, such as Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), and renin inhibitors, do not significantly stop the disease progression. A novel approach is being developed to counter different pathways using dual inhibitors, which interfere with different pathophysiological pathways to slow the development of DCM. Angiotensin II type 1 receptor (AT1R) – neprilysin (NEP) inhibitors (ARNi) have been developed to counteract the effects of angiotensin and increase the activity of natriuretic peptides (NPs). The US FDA approved the first ARNi, valsartan/sacubitril, in July 2015 for treating heart failure with reduced ejection fraction. The role of ARNi in DCM has been investigated with good results, with telmisartan and thiorphan administered individually and in combination yielding better protection than individual drugs. The proposed approach involves designing new chemical entities (NCEs) by combining the pharmacophores of US-FDA-approved drugs (Losartan and Thiorphan) using an in silico approach. These compounds will be screened for potential inhibitory activity against AT1R and NEP and evaluated in vitro and in vivo. Initial studies have shown encouraging results for inhibiting AT1R and NEP in silico studies, resulting in the development of newer lead candidates to inhibit DCM progression and offer a promise of better management of diabetic complications.