A Novel Target for Diastolic Heart Failure

Cardiovascular diseases are the leading cause of death in the developed world and are now on track to become the leading cause of death in the developing world. One particular manifestation, heart failure (HF), is dramatically increasing in frequency and is now the leading cause of hospitalisation in the over 60s. There is an even split between a) systolic heart failure, which is moderately well-served pharmacologically by a number of agents including loop diuretics, beta-blockers and ACE inhibitors, but despite these the 5 year survival rate (< 50 %) is worse than for most common cancers, and b) diastolic heart failure, which has no effective treatments and mortality comparable to that of systolic heart failure. It is becoming apparent that altered myocardial energetics plays a prominent role in the pathogenesis of HF, that optimisation of myocardial metabolic efficiency is a highly promising approach to treatment of HF, and that this approach can be additive or synergistic with other therapies.

We have discovered a drug which can shift myocardial metabolism from fatty acid to carbohydrate utilisation (improved substrate utilisation), enhancing ATP synthesis without affecting oxygen consumption (enhanced cellular energetics).  This has been shown to give a functional benefit even for heart failure patients already receiving optimal drug therapy.

Studies have demonstrated that this drug interacts with two isoforms of a particular enzyme, one responsible for the therapeutic and one for the toxic effects; preparation of closely related analogues has demonstrated that the two activities can in fact be separated. Our current studies focus on the synthesis of selective ligands, with the aim of validating the enzyme as a therapeutically relevant target for improving myocardial function and thus facilitating the development of a new generation of treatments for IHD and heart failure.

The program lead compounds were patented and licensed to Signal Pharma in 2013

Project Team: Dr Iain Greig, Prof Michael Frenneaux, Prof Matteo Zanda, Dr Chih-Chung Tseng

Publications: Tseng et al., Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy. Journal of Medicinal Chemistry 2017 doi: 10.1021/acs.jmedchem.6b01592

Funding: Signal Pharma, Roemex Ltd, Knowledge Exchange and Transfer and KCT Pump Priming Funds