1. 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
11/19/2018
MEDC 603 Fall 2006

2. 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
11/19/2018
MEDC 603 Fall 2006

3. 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
11/19/2018
MEDC 603 Fall 2006

4. Sulfonyl Ureas Ionization 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
11/19/2018
MEDC 603 Fall 2006

5. Structures of Sulfonyl Ureas
R R’
Tolbutamide
Chlorpropamide
Tolazamide
Glyburide
Glipizide
Glimepiride
11/19/2018
MEDC 603 Fall 2006

6. Major Pharmacokinetic Properties of Sulfonyl Ureas
Eqv. Dose
(mg)
Duration
(h)
Active metabolites
First Generation
Tolbutamide
12-24
No (p-COOH derivative)
Chlorpropamide
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)
11/19/2018
MEDC 603 Fall 2006

7. Substituted Benzoic Acids
Meglitinide
Structural similarity to SUs
Functional similarity to SUs
More rapidly active
Shorter duration of action
Less problematic hypoglycemia
Reduced weight gain
Replaglinide
Nateglinide
11/19/2018
MEDC 603 Fall 2006

8. Biguanides Phenformin Metformin Mechanism of Action (Metformin)
Unclear
Does not depend on insulin (synthesis or secretion)
Anti-hyperglycemic (not hypoglycemic)
Possibly two components: increased sugar usage and inhibition of gluconeogenesis
11/19/2018
MEDC 603 Fall 2006

9. 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)
11/19/2018
MEDC 603 Fall 2006

10. Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone
Troglitazone
Pioglitazone
11/19/2018
MEDC 603 Fall 2006

11. a-Glucosidase Inhibitors - Acarbose
Inhibitor of Sugar Absorption from the GI tract
a-glucosidase
11/19/2018
MEDC 603 Fall 2006

12. a-Glucosidase Inhibitors - Acarbose
Transition State of hydrolysis
Acarbose – transition state mimic
11/19/2018
MEDC 603 Fall 2006