Diabetic Disorders 4th Leading cause of deaths in the US 75% of those afflicted with diabetes die from CHD Major complications of diabetes Fearsome 15 Elevated triglycerides and LDL; reduced HDL; High blood pressure; obesity; kidney failure; blindness; peripheral neuropathy; decline in cognitive abilities; atherosclerosis; heart attack; stroke; peripheral vascular disease; poor wound healing; frequent infections 9/20/2018 MEDC 603 Fall 2007

Diabetes Mellitus Type I Diabetes aka IDDM (Insulin-dependent diabetes mellitus) Inability of b-islet cells of pancreas to produce insulin Type II Diabetes aka NIDDM (Non-insulin-dependent diabetes mellitus) Either a reduced ability of pancreas to produce or secrete insulin (some residual capacity) and/or reduced ability of target cells to respond to insulin Gestational Diabetes 9/20/2018 MEDC 603 Fall 2007

Diabetes Mellitus Insulin two chain polypeptide connected by two S-S bonds A chain = 21 AA residues; B chain = 30 AA residues may exist as dimer, trimer or higher oligomers in solution produced in b-islet of Langerhans Regulates glucose transport stimulates GLUTs Regulates gene transcription ~100 genes are known to be regulated by insulin e.g., insulin inhibits gluconeogenesis …. Liver overproduces glucose in insulin-resistant state (type 2 DM) Regulates glucose metabolism phosphorylation of G to G-6-P …. Signal transduction 9/20/2018 MEDC 603 Fall 2007

Overview for Controlling Hyperglycemia Absorption from Diet Biosynthesis in Liver a-Glucosidase Inhibitors Biguanides Cellular Uptake Serum Sugar Biguanides; thiazolidinediones Sulfonylureas; Benzoic Acids Pancreas Insulin {Hypoglycemia} 9/20/2018 MEDC 603 Fall 2007

pKa ~5 Sulfonyl Ureas Structure & Ionization Mechanism of Action _ pKa ~5 Mechanism of Action Stimulates release of insulin from b-cells Act through ion-channels that generate a Ca+2 influx Affinity to this receptor correlates with hypoglycemic effect In addition, there are extra-pancreatic effects, e.g., effects on glucose transporter 9/20/2018 MEDC 603 Fall 2007

Structures of Sulfonyl Ureas R R’ Tolbutamide Chlorpropamide Tolazamide Glyburide Glipizide Glimepiride 9/20/2018 MEDC 603 Fall 2007

NOTE: 1) Hypoglycemia 2) Weight Gain Major Pharmacokinetic Properties of Sulfonyl Ureas Eqv. Dose (mg) Duration (h) Active metabolites First Generation Tolbutamide 1000-1500 12-24 No (p-COOH derivative) Chlorpropamide 250-375 24-60 Yes (2’-OH and 3’OH groups) Tolazamide No (4-COOH derivative) Second generation Glipizide 10 10-24 No (cleavage of pyrazine ring) Glyburide (glibenclamide) Third generation 5 16-24 Some (trans + cis 4’-OH groups) Glimepiride 1-2 24 Yes (-OH on CH3 of R’ group) NOTE: 1) Hypoglycemia 2) Weight Gain 9/20/2018 MEDC 603 Fall 2007

Substituted Benzoic Acids or ‘Glinides’ Structural similarity to Sus pKa ~3-5 (close to SUs) Functional similarity to SUs More rapidly active Shorter duration of action Less problematic hypoglycemia Reduced weight gain Meglitinide Replaglinide Nateglinide 9/20/2018 MEDC 603 Fall 2007

Biguanides Phenformin Metformin Mechanism of Action (Metformin) (not available in the US) (introduced in the US in 1995) Mechanism of Action (Metformin) Unclear Phenformin induces lactic acidosis …. Fatal in 3% Does not depend on insulin (synthesis or secretion) Anti-hyperglycemic (not hypoglycemic …. note !!) Possibly two components: increased sugar usage and inhibition of gluconeogenesis 9/20/2018 MEDC 603 Fall 2007

Thiazolidinediones (glitazones) R group Mechanism of Action Pioglitazone (racemic) Ciglitazone (racemic) Mechanism of Action Enhance glucose and lipid metabolism through action on PPARg Enhance sensitivity to insulin in target cells Troglitazone (racemic) Rosiglitazone (racemic) 9/20/2018 MEDC 603 Fall 2007

Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone Troglitazone Pioglitazone 9/20/2018 MEDC 603 Fall 2007

a-Glucosidase Inhibitors - Acarbose Inhibitor of Sugar Absorption from the GI tract a-glucosidase 9/20/2018 MEDC 603 Fall 2007

a-Glucosidase Inhibitors - Acarbose Transition State of hydrolysis Acarbose – transition state mimic 9/20/2018 MEDC 603 Fall 2007