Design, synthesis and testing of calpain inhibitors for the treatment of cataract

Abstract

This thesis reports the development of potent and selective inhibitors of m-calpain for the treatment of cataract. SJA6017 has been proven to prevent lens opacity in rat and has been our lead compound. A series of Val-Leu peptidyl aldehyde inhibitors (33a-e, 33g, 33i and 35) have been designed, synthesized, and tested for therapeutic potential as cataract inhibitors. Chapter 1 is an introduction to calpain and the diseases associated with it's over activation. A review of the literature on calpain inhibition is given. Structure activity relationship (SAR) theory is presented. The techniques that have been applied in our research group to drug design include molecular modeling, synthesis, assay and animal studies which are all briefly discussed. The importance of a -strand conformation for an inhibitor to bind to calpain is discussed. Chapter 2 describes the synthesis of m-calpain inhibitors. This comprises the preparation of the Val-Leu dipeptide core 29, Val-Leu dipeptidyl alcohols 31a-g and 31i, and the synthesis of dipeptidyl aldehydes 33a-e, 33g, 33i and 35. The choice of coupling regents and conditions in the coupling reactions is investigated. Sulfur trioxide pyridine oxidation for the conversion of Val-Leu dipeptidyl alcohols to aldehydes is discussed. The molecular modeling and biological assay results are presented.