MEDICINAL CHEMISTRY “Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes" Made by : Iren Meylani.

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MEDICINAL CHEMISTRY “Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes" Made by : Iren Meylani Nim : O1A Class : B

Introduction: diabetes—an emerging epidemic of the 21st century Diabetes mellitus (often referred as diabetes) is a group of metabolic diseases characterized by abnormally high levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test.

The World Health Organization recognizes mainly two distinct clinical forms of diabetes, for example, type 1 and 2). Diabetes mellitus Type I (insulin-dependent diabetes or juvenile onset diabetes) - Caused by destruction of beta cells - Generally appears in childhood -Absolutely dependent on insulin replacement Type II (insulin-independent diabetes or adult onset diabetes) - Caused by target cell resistance to insulin (signaling defect) - Mostly obese patients (likely genetic predisposition) - Obesity appears to reduce the number of insulin receptors - Can be treated with oral hypoglycemic drugs Chart 1. Classification of diabetes mellitus.

Current treatments of T2D: insufficient for glycemic control? Enhancement of insulin secretion by pancreatic islet b-cells has been a major goal for the treatment of T2D. The current therapeutic agents,2a although effective in increasing insulin secretion, are associated with undesirable side effects, including hypoglycemia, abnormalities in cardiovascular responses and b-cell apoptosis

Dipeptidyl peptidase—4: a new therapeutic target in type 2 diabetes Serine proteases are class of enzymes that cleave peptide bonds in proteins and as implicated by the name, one of the critical amino acids in the active site of the enzyme that cleaves peptide bonds is serine. The dipeptidyl peptidases (DPPs) are a subclass of the serine protease family.

Glucagon: playing the opposite role of insulin in glucose regulation Glucagon plays a major role in maintaining normal glucose levels in blood via increasing it when blood glucose levels begin to fall below the normal range

Glucagon maintains the normal blood glucose level with the help of two pivotal metabolic pathways within the liver: (a) as soon as secreted, it binds to glucagon receptors on hepatocytes to activate the enzymes that depolymerize glycogen stored in the liver through a process called glycogenolysis and (b) as the glycogen storage in the liver is depleted, glucagon then encourages the liver to synthesize additional glucose from nonhexose substrates such as amino acids via gluconeogenesis. The glucose generated is released into the bloodstream thus preventing the development of hypoglycemia.

GLP-1: the most important incretin hormone and substrate of DPP-4 GLP-1 is an incretin hormone (Fig. 2) secreted by intestinal L-cells of the distal small intestine in response to food intake, that is, oral nutrients.4 While oral nutrients such as glucose and fat are potent physiological regulators of GLP-1 secretion, neuromodulators acetylcholine and gastrin releasing peptide (GRP) have also been identified as nonnutrient stimulators of GLP-1

GIP: the other incretin hormone and substrate of DPP-4 The first and the other most important incretin hormone GIP was purified and characterized in 1970s. Until that the identity of the putative incretin factor(s) remained elusive. Initially GIP was believed to neutralize stomach acid to protect the small intestin from acid damage, reduce the rate at which food is transferred through the stomach, and inhibit the GI motility and secretion of acid