L10 - Development Of Ace Inhibitors

Question 1

What are the key properties required for ‘drug-like’ molecules?

Answer 1

Selectivity and high affinity for the target.
Oral administration (chronic disease).
Water solubility for formulation and lipophilicity for absorption.
Stability in the gastrointestinal environment.
Slow metabolism for sustained activity.
No toxic metabolites.

Question 2

Why is ACE a good drug target?

Answer 2

Converts angiotensin I to angiotensin II, affecting blood pressure.
Abundant in the lungs and other vascular tissues.
Accessible on endothelial cell membranes.
Enzyme inhibition can reduce blood pressure.

Question 3

How does ACE hydrolyse angiotensin I?

Answer 3

Hydrolyses the peptide bond between phenylalanine (Phe) and histidine (His).
Zinc ion at the active site facilitates this process.

Question 4

What are the subsite pockets in ACE’s active site?

Answer 4

S1: Binds aromatic groups.
S1’: Binds aromatic or aliphatic groups.
S2’: Binds aliphatic groups and carboxylate groups (via a basic side chain).

Question 5

What is captopril, and how does it inhibit ACE?

Answer 5

The first ACE inhibitor developed, containing a thiol group that interacts with zinc.
Potency (IC50): 0.023 μM.
Key features: Proline carboxyl group, thiol group, and methyl group for potency.
Issues: Side effects like rashes and taste loss due to the thiol group.

Question 6

How was enalapril developed from enalaprilat?

Answer 6

Enalaprilat was highly potent but poorly absorbed due to its hydrophilic carboxyl group.
Enalapril, a prodrug, temporarily masks the carboxyl group with an ethyl ester, improving absorption.
Liver esterases convert enalapril into the active enalaprilat.

Question 7

What are the pharmacokinetic properties of enalapril?

Answer 7

Dose: 2.5 mg once daily.
Bioavailability: 60%.
Half-life (enalaprilat): 12 hours.
Elimination: Renal excretion.

Question 8

How do other ACE inhibitors (e.g., ramipril) improve on earlier designs?

Answer 8

Ramipril is an ester prodrug converted to ramiprilat.
Added lipophilic groups enhance interaction with the S2’ pocket, increasing potency and absorption.

Question 9

Why is zinc important in ACE activity?

Answer 9

Zinc ion in the active site binds electron-rich/negatively charged groups, stabilising the transition state and facilitating hydrolysis.

Question 10

What are the challenges with ACE inhibitors like captopril and enalaprilat?

Answer 10

Captopril: Side effects from the thiol group.
Enalaprilat: Poor absorption due to hydrophilicity.
Both issues were addressed by developing prodrugs and optimising active site interactions.