Medicinal Chemistry of Non-insulin

Pharmacological treatment of type 2 diabetes requires what?

Hyperglycemia management

Classes of hypoglycemic agents

Sulfonylureas;Biguanides;GLP-1 analogues;DPP-IV inhibitors;SGLT2 inhibitors

Sulfonylureas examples

Glyburide;Glipizide;Glimepiride

Sulfonylureas are what type of compounds?

Weak acids

Sulfonylurea pharmacophore

Benzenesulfonylurea

Mechanism of sulfonylureas

Bind SUR1 receptor on pancreatic beta cells and inhibit KATP channels leading to insulin release

Glimepiride metabolism

Metabolized by CYP2C9 to active M-1 then inactive M-2

Biguanides contain what?

Two guanidine groups

Only biguanide used

Metformin

Metformin is what type of drug?

Basic drug

Metformin mechanism

Reduces hepatic glucose production by decreasing gluconeogenesis and stimulating glycolysis;enhances insulin sensitivity

Metformin adverse effect

Lactic acidosis

GLP-1 is what?

Endogenous incretin secreted from intestinal L-cells

Function of GLP-1

Regulates glucose homeostasis and stimulates insulin secretion

GLP-1 structure

30 amino acid polypeptide

GLP-1 forms

GLP-1(7–36)-NH2 and GLP-1(7–37)

GLP-1 half-life

1-2 minutes due to DPP-IV degradation

Why use GLP-1 agonists or DPP-IV inhibitors?

To control blood glucose levels

GLP-1 degradation mechanism

DPP-IV removes dipeptide from N-terminus

Why GLP-1 unstable?

Contains Ala at position 8

Substitution at Ala8 effect

Increases stability and resistance to DPP-IV

Liraglutide description

Acylated GLP-1 (7-37) derivative

Liraglutide modification

Fatty acid chain at Lys26 increases albumin binding and reduces renal elimination

Liraglutide resistance mechanism

Lys34 replaced with Arg increases DPP-IV resistance

Dulaglutide description

GLP-1 IgG4 Fc fusion protein

Dulaglutide advantage

Protects from DPP-IV degradation

Dulaglutide half-life

~5 days

Dulaglutide dosing

Weekly SC injection

Semaglutide description

Long-acting GLP-1 analogue

Semaglutide modification

Ala8 replaced with Aib increases DPP-IV resistance

Semaglutide additional feature

C18 fatty diacid chain increases albumin binding

Semaglutide half-life

~165 hours

Semaglutide dosing

Once weekly SC

Oral semaglutide (Rybelsus) feature

Co-formulated with SNAC

SNAC function

Increases pH, enhances absorptin, protects drug from breakdown

Dual GLP-1/GIP agonist

Tirzepatide

Tirzepatide structure

39 amino acid polypeptide

Tirzepatide advantage

Greater reduction in hyperglycemia than GLP-1 alone

Tirzepatide receptor affinity

Higher for GIP than GLP-1

GLP-1 analogues limitation

Require SC administration and may be immunogenic

DPP-IV inhibitors examples

Sitagliptin;Saxagliptin;Linagliptin;Alogliptin

DPP-IV inhibitor function

Block GLP-1 degradation

DPP-IV inhibitor SAR

Electrophilic group (cyano);Basic amino group;Hydrophilic central pharmacophore

Saxagliptin metabolism

CYP3A4 to 5-hydroxysaxagliptin

Alogliptin metabolism

N-demethylated (M-1) and N-acetylated (M-2)

SGLT2 location

Proximal convoluted tubule of kidney

SGLT2 function

Reabsorbs 80-90% of glucose

SGLT2 inhibition effect

Reduces hyperglycemia

Phlorizin description

Natural glycoside SGLT2 inhibitor

Phlorizin limitation

Hydrolyzed in GI tract

Gliflozins modification

C-glycoside linkage increases stability

SGLT2 inhibitors examples

Canagliflozin;Dapagliflozin;Empagliflozin;Ertugliflozin;Bexagliflozin

Gliflozins metabolism

Glucuronidation by UGT enzymes