Design and Synthesis of CCK- 8 Derived Peptidomimetics as Selective Inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B) for the Development of Anti-diabetic Agents

Abstract

Diabetes is a disease characterized by high levels of blood glucose resulting from defects in insulin production, insulin action or both. Type 2 diabetes is typically a polygenic disease that results from a complex interplay between genetic predisposition and environmental factors such as diet, degree of physical activity and age. People with diabetes will increase from 175 million in 2000 to 350 millions in 2030, with the biggest increase expected in India and China. The rising incidence of type 2 diabetes has begun to surface in children at an alarming rate, in some countries representing up to 80% of all the cases of diabetes reported in the pediatric population. The first chapter of this thesis gives an overview of the role of Protein Tyrosine Phosphatase 1B (PTP1B) and its inhibitors in the development of anti-diabetic agents with the main emphasis on the present status of PTP1B inhibitors. The second chapter of the thesis deals with the development of synthetic methodology and biological evaluation of O-Malonyl and O-Carboxymethyl derivatives as PTP1B inhibitors. This chapter is divided into three parts. The chapter begins with a concise introduction of O-Malonyl tyrosine as phosphotyrosyl mimics. The second section deals with the study of the effect of free amino components of the most potent analogues synthesized and evaluated in the first section. Beside these compounds, conformationally constrained derivatives were also investigated in the second part. To address the issue of bioavailability, the malonyl group of more potent analogues was replaced with the acetate group. In these three sections, each part describes the basis of work, chemistry, results and discussion as well as the experimental details and biological activity. The important feature that came out from the second chapter was that, the lipophilicity plays an important role both in terms of inhibitory activity as well as selectivity against PTP1B. Therefore the third chapter is in continuation of the findings emerging from the results described in Chapter 2. The normal peptide bond, which is susceptible to peptidases, was replaced with modified peptide bonds viz. N-methyl amino acid containing peptide and incorporation of β-amino acid in the target molecules. In these two sections, each part describes the basis of work, chemistry, results and discussion as well as the experimental details and biological activity. In the fourth chapter, we have discussed the synthesis of new PTP1B inhibitors with modified phosphate group viz. phosphate esters and phosphonates. We have chosen the same dipeptide which was explored for the lipophilic derivatives and incorporation of surrogate phosphate groups viz. O-Malonyl and O-Carboxymethyl. In the fifth chapter, we have discussed the synthesis and evaluation of the tetrapeptide inhibitor H-Trp-Lys-Pro-Asp-OH, which is derived from the molecular modeling studies and has shown excellent binding affinity for PTP1B. Therefore it was imperative to validate the theoretical predictions.This tetrapeptide is unique in respect to its chemical structure due to the absence of any phosphate mimic pharmacophore, therefore it was considered essential to validate the predicted inhibition with the experimental data.