🔬 Med Chem of Antidiabetics

Structure:
A and B chain connected with disulfide bonds
🔗 (A7-B6, A20-B19)

A chain - 21 aa

B chain 30 aa

Oligomeric Insulin

  • Monomer
    ⭐ Insulin only binds in monomeric form

- Higher oligomer
NO activity

[monomer] > 100 nM

[monomer] < 100 nM

Dimer

Insulin likes to dimerize

Hexamer
3 dimers combine in presence of Zn2+

Stability

  • Unfolding/Denaturization of Insulin
    • Heat
    • Shear forces
    • Hydrophobic surfaces

Prevent denaturation:
✅ Proper storage (4'C)

Prolonged storage ( > 4 mos)
-> Deamidation of Asn (A21)*
-- 1-2%
-- 25'C, 6 mos: 90%

Most soluble so shortest onset, DOA

Deamidation of Asn residues
-- EXCEPT Asn (B3)

Asn (B3) deamidation gives aspartate and isoaspartate
-- active modified insulins

Absorption

Depends on concentration and form of insulin

⬆ [insulin]
-- more polymeric (less soluble)
-- lower absorption

Human insulin vs. Non-human insulin

Different residues in non-human, modified insulin

If residues are not important for activity, non-human insulin can still be used

SARs

  • ⬇ Activity
    -- Removal of 8 residues from C-terminus of B chain destroys activity
    -- Removal of N-Gly from A chain **diminishes activity

Mutations to arginine change activity

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INSULIN

✒

ORAL ANTIDIABETICS

💊

a-Glucosidase Inhibitors

Biguanides

Thiazolidinediones

DPP-4 Inhibitors (-gliptins)

Sulfonylureas

Core Structure

⭐ Sulfonyl group

⭐ Urea group

Antibiotics
-- have a sulfonyl but no urea
-- amine at C-4 (inflammation)

R, R' groups can be alkyl chains or aromatic rings

Antibiotics mimic precursor of folic acid, PABA

Core Structure

⭐ Two guanides

Core Structure

Core Structure

Core Structure

MOA: directly interacts with v-ATPase and activates ATPK

SAR with recently discovered MOA is unclear

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💡 Critical SAR studied from PPAR-y binding to pioglitazone

⭐ Transition state (of sugar hydrolysis) mimic
-- transition state competitive inhibitor

Substitution of O to N

Substitution of C to N

💡 Critical SAR studied from
a-glucosidase binding to acarbose

DPP-4 MOA

DPP-4 deactivates incretin by removing first 2 residues

⭐ Mimic of the 2 aa residues that are removed by DPP-4

💡 Critical SAR studied from DPP-4 binding to sitagliptin

⭐ Prefers proline at P1 site

⭐ NH2 at P2 site

Cyanopyrrolidine PI
-- potent due to transient covalent trapping of nitrile group by the active site Ser360
(slow tight-binding kinetics of reversible cov bonds)

DPP-4 can also bind to CD26 (T cell activation marker), causing immunological effect

Bovine insulin has 3 different residues from hIn

Porcine insulin has 1 different residue from hIn