Angiotensin converting Enzyme inhibitors

ACE inhibtors sar moa synthsis

1. Drugs acting on Renin Angiotensin System 1. Angiotensin converting Enzyme Inhibitors (ACEI) 2. Angiotensin-II Receptor Blockers (ARBS) 1.ACE Inhibitors Based on the Zn 2+ binding groups Sulphydral containing inhibitors: Capto pril Dicarboxylate containing inhibitors: Enala pril , Lisino pril , Rami pril , Quina pril , Perindro pril Phosphate containing inhibitors: Fosin pril Capto pril & Lisino pril are non prodrugs Remaining drugs are prodrugs

2. Captopril -SH group enhance binding to Zn 2+ In the ACE The carboxylate ion (COO - ) attract the cationic site of the ACE by arginine residue, b/s of above attachments, the carbonyl group becomes polarized and more susceptible to hydrolysis instead of angitensin -I 2-CH3 is important for action. Substitution of other amino acid with proline decrease the activity.

3. SAR The N-ring must contain carboxylic acid The N-ring should be large hydrophobic rings b/s it increase the potency by altering pharmacokinetic parameters

4. The A, B, C groups can serve as Zn 2+ binding sites The thiol group shows superior binding to Zn 2+ among the carboxylate and phosphate. Estrification of carboxylate (B) and phosphate (C) produces orally active products The X should be –CH 3 In carboxylate derivatives X should be n- butylamine The n usually 2 for activity

5. ACEI

6. Angiotensinogen Angiotensin I Angiotensin II Renin ACE X MOA OF ACEI Aldoserone Na reabsorption Blood volume Cardiac output BP ACEI Aldoserone Na reabsorption Blood volume Cardiac output BP

7. Therapeutic Uses Anti-hypertensive Prevent or reverse LVH Protect against sudden death and second myocardial infarction after acute MI Improve survival and hemodynamics in patients with congestive heart failure Protect against progression of diabetic nephropathy

8. Adverse Effects Hypotension Renal Insufficiency (if bilateral renal artery stenosis ) Hyperkalemia – special group of patients (Na restricted, on K-sparing diuretic, COX inhibitors) Cough (20 %) Angioedema With captopril especially: neutropenia , nephrotic syndrome, skin rash, taste disturbances (SH group- related).

9. 2. Angiotensin-II Receptor Blockers (ARBS) Losartan Valsartan Telmisartan Candesartan Olmesartan

10. MOA Angiotensin II receptor blockers (ARBs) act differently from ACE inhibitors. These drugs block the angiotensin-II binding to its receptor, Aldoserone production Na reabsorption Blood volume Cardiac output BP

11. Angiotensin II receptor blockers can be used to treat  coronary artery disease ,  heart failure ,  high blood pressure , kidney disease . Side effects Chest pain Back pain Peripheral edema Facial edema Dry cough (less common)

12. Synthesis of Captopril