Medchem Flashcards
AchEi SAR (+examples)
- Good leaving group (benzene ring/phenol)
- Blocking group (Carbamate)
- Positive charge (Amine)
What is a good blocking group for an AchEi
Carbamates are good blocking groups…
* The electron pair on the N
* Delocalised resonance = Electronegativity more spread
* Carbonyl carbon less electronegative = Less susceptible to nucleophilic attack (from water = hydrolysis)
What is a good leaving group for AchEi
Benzene rings or phenols bc
Can neostigmine & pyridostigmine cross the BBB and why
They can’t bc of the permanently charged Nitrogens and therefore are selective for the peripheral nervous system
Aspirin MOA
- Tyrosine residues form hydrogen bond network = positioning it for reaction with Ser529
- Aspirin carboxylate anion increases Ser O nucleophilicity
- Serine attacks = transesterification of carboxyl group
- salicylic acid is cleaved leaving acylated serine
= Arachidonic acid is blocked from accessing the Haem moeity.
TRUE OR FALSE
Aspirin is a selective COX-1 competitive inhibitor
FALSE
It is non-selective & binds irreversibly
NSAID SAR
- Carboxylic acid - Ionic interaction w/ Arginine120
- Ortho-substituated benzene - steric bulk
- Lipophilic group
COX-2 inhibitor SAR
Sulfonamide group - for hydrophobic pocket via ionic interactions
5-6 membered ring
Cis-stilbene structure
Aspirin SAR
Salicylic acid
Carboxylate anion
Phenol
Ester
Differences between Aspirin and other NSAIDs MOA
- Asprin binds to Ser529 | NS to Arg120
- Aspirin block access to the heme-moeity with acylated Ser
- NS block the hydrophobic channel in COX
- Aspirin is irreversible inhibitor | NS are reversible
H2 antagonist SAR
- Tautomer I methylation - Increases N basicity which favours tautomer I w/o increasing ionisation too much.
- Electron withdrawing atom (S) middle of the chain - reduces basicity of nearest N ∴ reduces imidazole ring ionisation = Locks it in tautomer I orientation.
- Thiourea bioisostere - Mantains delocalised resonsance + H-bonding potential w/o the toxicity
- 4C chain extension - Pushes cyanoguanidine into antagonist binding region = Increases selectivity
PPI SAR
- Benzimidazole
- Methylsulfinyl link
- Pyridine + MeO at ortho + methyl substituents = Resonance effect Increases electron density of ring ∴ Increase N nucleophilicity (more likely to attack)
- MethyOxyl (e- donating) on left and right push electron density inward = Favorable for reaction
What does leflunomide inhibit
Dihydroorotate dehydrogense
Not assessible
Leflunomide
Pro-drug with two active metabolites.
Z-teriflunomide is more active and more dominant in vivo than E-teriflunomide.
Leflunomide SAR
- Lipophilic group at aromatic ring
- Para substituency to aromatic ring
- Aromatic ring - loss of activity otherwise
- Central amide essential for activity
- Triple bond amine essential
How does Azathiopurine work
It is slowly converted by glutathione (GS-) into the active metabolite; 6-Mercaptopurine. 6-MCP is rapidly metabolised ∴ a prodrug reduces the levels of available 6-MCP and controls these pathways.
What does Azathiopurine react with
Glutathione (GS-)
Azathiopurine SAR
- O-N=O essential
- Heterocyclic group must be electron withdrawing (to drive the reaction)
MTX MOA
It works by mimicking folic acid and competitively inhibiting DHFR, thereby preventing the synthesis of purines & pyrimidines.
It is therefore anti-proliferative.
How does folic acid differ from MTX
Methotrexate differs by an additional amine and methyl group.
= Additional ionic + H-bond
= Higher affinity for DHFR
Which metabolite of Leflunomide provides the most activity
Z-Teriflunomide, although both are active.
What increases the risk of a thrombotic event in NSAIDs
COX-2 inhibition has a larger impact on the kidneys which in turn affects the cardiovascular system.
* Increase in BP is commonly seen
* Thrombotic events cautioned (prescribe appropriately)
When is paracetamol preferred over NSAIDs
Preferred in patients …
* Elderly
* Co-morbidities: Hypertension, High CVD risk, Renal impairment
* Patients with already existing GI issues
* Patients with contra-indicated medicines (e.g. Anticoagulants - warfarin )
