Diabetic Disorders 4 th Leading cause of deaths

Diabetic Disorders • • 4 th 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 10/17/2021 MEDC 603 Fall 2007 1

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 10/17/2021 MEDC 603 Fall 2007 2

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 10/17/2021 MEDC 603 Fall 2007 3

Overview for Controlling Hyperglycemia Absorption from Diet Biosynthesis in Liver a-Glucosidase Inhibitors Biguanides Serum Sugar Pancreas Sulfonylureas; Benzoic Acids Biguanides; thiazolidinediones Cellular Uptake Insulin {Hypoglycemia} 10/17/2021 MEDC 603 Fall 2007 4

Sulfonyl Ureas Structure & Ionization p. Ka ~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 10/17/2021 MEDC 603 Fall 2007 5

Structures of Sulfonyl Ureas R R’ Tolbutamide Chlorpropamide Tolazamide Glyburide Glipizide Glimepiride 10/17/2021 MEDC 603 Fall 2007 6

Major Pharmacokinetic Properties of Sulfonyl Ureas Eqv. Dose (mg) Duration (h) Active metabolites 1000 -1500 12 -24 No (p-COOH derivative) Chlorpropamide 250 -375 24 -60 Yes (2’-OH and 3’OH groups) Tolazamide 250 -375 12 -24 No (4 -COOH derivative) 10 10 -24 No (cleavage of pyrazine ring) 5 16 -24 Some (trans + cis 4’-OH groups) 1 -2 24 Yes (-OH on CH 3 of R’ group) First Generation Tolbutamide Second generation Glipizide Glyburide (glibenclamide) Third generation Glimepiride NOTE: 1) Hypoglycemia 10/17/2021 2) Weight Gain MEDC 603 Fall 2007 7

Substituted Benzoic Acids or ‘Glinides’ • Structural similarity to Sus Meglitinide • p. Ka ~3 -5 (close to SUs) • Functional similarity to SUs • More rapidly active • Shorter duration of action Replaglinide • Less problematic hypoglycemia • Reduced weight gain Nateglinide 10/17/2021 MEDC 603 Fall 2007 8

Biguanides Phenformin 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 10/17/2021 MEDC 603 Fall 2007 9

Thiazolidinediones (glitazones) R group Pioglitazone (racemic) Ciglitazone (racemic) Troglitazone (racemic) Mechanism of Action Enhance glucose and lipid metabolism through action on PPARg Enhance sensitivity to insulin in target cells Rosiglitazone (racemic) 10/17/2021 MEDC 603 Fall 2007 10

Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone Troglitazone Pioglitazone 10/17/2021 MEDC 603 Fall 2007 11

a-Glucosidase Inhibitors - Acarbose Inhibitor of Sugar Absorption from the GI tract a-glucosidase 10/17/2021 MEDC 603 Fall 2007 12

a-Glucosidase Inhibitors - Acarbose Transition State of hydrolysis Acarbose – transition state mimic 10/17/2021 MEDC 603 Fall 2007 13