Minimizing myocardial damage and loss of cardiac function post myocardial infarction using Targeted PKC inhibitors 002 and 004.

Abstract. This Phase II SBIR proposal focuses on the advanced development and validation of YT-002 and YT-004, innovative compounds targeting Protein Kinase C epsilon (PKCε) and Protein Kinase C beta II (PKCβII), respectively, to preserve myocardial tissue and function following infarction. The research is meticulously planned to not only refine the pharmacokinetic/pharmacodynamic (PK/PD) profiles of these agents but also to conduct in-depth long-term safety and efficacy studies in porcine models, paving the way for Investigational New Drug (IND) applications. Specific aims include: 1) Optimization of drug formulations to enhance stability, ensuring effective delivery and action within the myocardium. 2) Detailed pharmacokinetic studies to thoroughly investigate absorption, distribution, metabolism, and excretion (ADME) properties, providing a solid foundation for dosing regimens. 3) Comprehensive pharmacodynamic assessments to evaluate the long-term impact of YT- 002 and YT-004 on myocardial infarct size and cardiac function, emphasizing sustained cardiac protection over extended periods. The project leverages advanced modeling techniques to establish a robust correlation between drug dosage/concentration and therapeutic outcomes, enabling the prediction and optimization of effective therapeutic windows. This includes employing non-linear mixed-effects modeling for PK data and analysis of variance (ANOVA) for PD endpoints, ensuring precise quantification of the drugs' cardioprotective effects. By systematically addressing these objectives, the proposal aims to confirm the long-term benefits of YT-002 and YT-004 in reducing myocardial damage, and the incidence of heart failure substantiating their potential as groundbreaking treatments for myocardial I/R injury. Success in these endeavors will not only facilitate the transition of these compounds to clinical trials but also potentially set new benchmarks in the treatment of cardiovascular diseases, significantly improving patient outcomes and quality of life post-myocardial infarction. Overall, this project represents a comprehensive effort to bring novel, targeted therapies from preclinical development into clinical readiness, offering promising new avenues for the effective management of myocardial I/R injury. Through rigorous research and innovative approaches, we aim to advance the understanding and treatment of this critical cardiovascular condition, ultimately contributing to enhanced health, prolonged life, and a reduction in the morbidity and mortality associated with myocardial infarction.