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Ischemic heart disease (IHD) is the leading cause of premature mortality in all regions and major public health problem with unacceptably high mortality and morbidity and burden to the health system, despite significant advances in treatment and management. This huge unmet medical need urgently requires novel strategies to improve mortality, morbidity and quality of life. This project will develop novel therapeutic agents targeting key inflammatory signalling pathways, p38MAPK, pivotal to IHD such as acute myocardial infarction (AMI) and subsequent progression to heart failure (HF).

Based on computer-assisted design and structure-activity relationships of novel pharmacophores, we have developed agents that are selective and potential inhibitors of p38MAPK and minimise the potential for abnormal liver function (a major cause of cessation of p38MAPK inhibitor development programs). We have developed compounds with pharmacophores that are not chromosomal and genetic toxiphores and have no known off-target and CYP450 liabilities. Cell-based and in vivo studies have demonstrated its efficacy and low toxicity. Thus, the lead compound (VCP979) possesses drug-like properties and further optimisation as proposed in this application is expected to produce suitable clinical candidate/s. This proposal will optimise the pharmacokinetic and ADMET profiles of VCP979, whilst maintaining or improving activity and selectivity. A series of in vitro and in vivo disease models will be used to validate its efficacy. It is expected drug candidates will be identified, investigation of new drug (IND) profiling performed and readied for phase I clinical trial.

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