Week 3 - DPP4 inhibitors (Gliptins) & GLP-1 receptor agonists for the treatment of Type 2 Diabetes Flashcards
KEY INFO
GIP and GLP-1 are hormones in the Gastro Intestinal Tract (GIT)
What is the role of GLP-1
GLP-1 = most important incretin
- Slows down gastric emptying (= ↓ appetite = weight loss)
- ↑ insulin secretion
- ↓ glucagon secretion
GLP-1 is suscpetible to amidation (adding amide group at end) AND cleavage of amide bond (hydrolysis)
- cleavage produces 2 active peptides
- GLP-1 (7-36) amide = active form
- laregly secreted + triggers pancreas to secrete insulin
- this form is rapidly degraded by DPP4 to form inactive GLP-1 (9-36)
- GLP-1 (7-37)
Describe the chemical property of DPP4
Inc. bonding, shape, functional groups, ionisation, lipophilicity
DPP4 rapidly degraded active GLP-1 (7-36 amide) to form inactive GLP-1 (9-36)
- 2 a.acids chopped off from start of active form
DPP4 is a serine protease = has a catalytic triad (3 a.acids adjacent in active site) ~ involved in amide hydrolysis
- A.acids = aspartate, histidine, serine
- aspartate hydrogen bonds to histidine
- histidine deprotonates serine (alcohol group ~ OH)
- deprotonated OH (O-) acts as nucleophile, eliminates Glu-9 (a.acid)
- ester bond in Ala-8 is hydrolysed = dipeptide formed (Hist-Ala)
SUMMARY: deprotonated OH group on serine a.acid (in DPP4) acts as a nucleophile + catalyses hydrolysis of ester bond = Glu-9 a.aci is removed from GLP-1
GLP-1 a.acids = HIS, ALA and GLU
How does DPP4 interact with its biological target
- It catalyses the hydrolysis of the amide bond in GLP-1 (7-36) amide
- Hydrolyses GLP-1 and GIP
AIM of DPP4 Inhibibitors
- inihbit DPP4 = will have higher active GLP-1 conc. in body
- in type 2 need a higher conc. to provide more insulin
Describe the chemical properties of Gliptins (DPP4 inhibitors)
Inc. bonding, shape, functional groups, ionisation, lipophilicity
Inhibit DPP4 = ↑ insulin secretion + ↓ glucagon secretion
Used in type 2 (in combination with other drugs)
Gliptins are orally actiove = need to consider lipinski rule of 5
1. NO > 5 hydrogen bond donors
2. NO > 10 hydrigen bond acceptors
3. Molecular weight < 500 g/mol
4. LogP < 5 (if above = too lipophilic = get stuck in membrane)
List the 5 Gliptins available
- Alogliptin
- Saxagliptin
- Vildagliptin
- Linagliptin
- Sitagliptin
How does Alogliptin interact with its biological target
CLUE: if structure has thick, black wedge line = CHIRAL CENTRE
MOST COMMONLY used gliptin
- Pyridine ring has cynao group (nitrile ~ triple bond)
- Benzene ring has primary amine (NH2)
- when protonated with benzoate salt = NH3+ - Has 1 chiral centre
How does Saxagliptin interact with its biological target
2nd most commnoly prescribed gliptin
- Has several chiral centres
- Primary amine (NH2) on secondary chiral centre
- Has a nitrile group
- Adamantane group (chair structure) = lipophilic
How does Vildagliptin interact with its biological target
- Has nitrile group
- Has secondary amine (NH)
- Has an amide (R-N-C=O)
- Has adamantane group
What is the function of nitrile group on Alogliptin, Saxagliptin and Vildagliptin
Nitrile group - C≡N
All 3 amino acids on DPP4 (ASP, HIS, SER) create good nucleophiles to add to C≡N (nitrile) group
- forms: a.acid-C=N
- forms a covalent inhibitor (bond is weak = covalent reversible)
Allows Gliptin (inhibitor) to covalently bind to DPP4 = inihbit its degrading mechanism
How does Linagliptin interact with its biological target
Commonly prescribed drug
- Has alkene (double bond)
- Has primary amine (NH2)
- Has purine ring
How does Sitagliptin interact with its biological target
Common drug prescribed
- Has primary amine group (becomes NH3+)
- Has 6 F (fluorine) atoms = lipophilic group
- 3 F on phenol ring for stability (ring is prone to metabolism in liver by CYP450 = prevent ring oxidation)
- 3 F = triflutomethyl group
- F is a metabolism blocker
Describe the discovery and design of a ‘biologics’ (GLP-1 Agonist)
Suffix is tide
Act in same way GLP-1 behave
- slows gastric emptying
- increase insulin + supress glucagon secretion
- All agonsit are peptides = why they are biologics
- Can NOT be given orally = given as S/C injection
- BNF safety warning - signs and symtpoms of DKA (diabetic ketoacidosis)
- inc. fruity smelling breath, polyuria, thirsty, blurred vision, tiredness, stomach pain
Can be given with or without other drugs for type 2]
- E.g. Semaglutide, Dulaglutide, Exenatide and Lixisenatide
Liraglutide is targeted / licensed for weight loss (specifically)
- can only be prescribed via specialist weight management service
- ONLY prescribed if: diet / excercise didn’t work, weight loss surgery not an option, ethnic origin
