Angiotensin II receptor blocker

PHRM 304

Angiotensin II receptor
The angiotensin receptors are a class of G protein-coupled receptors with angiotensins as ligands.

Angiotensin II receptor
In the early 1990s, the receptor for angiotensin II was found to exists as four isozymes AT1, AT2, AT3 and AT4 AT1 being responsible for smooth muscle contraction, sympathetic pressor mechanism and aldosterone release.

Mechanism of action of ARBs

ARBs displace angiotensin II from the AT1 receptor (by competitive antagonism) and produce their blood pressure lowering effects. All currently available ARBs are 10,000-fold more selective for the AT1 receptor subtype.

Development of ARBs
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Angiotensin II

Binds with Angiotensin receptor (AT1) and increase blood pressure

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Angiotensin II
Aspartic acid1 & Phenylalanine8 were replaced with Sarcosine and Isoleucine respectively

An octapeptide analogue of Angiotensin II

Sar-Arg-Val-Tyr-Ile-His-Pro-Ile
Saralasin

Saralasin
Peptide analogue Act as antagonist of AT1 receptor Lack of oral bioavailability Act as partial agonist

Non-peptide antagonist was demand

Imidazole-5-acetic acid analogues

In 1982: Patent publication

Imidazole-5-acetic acid analogues

Non-peptide Specifically block AT1 receptor Weak antagonist No agonist activity

3 important features of S-8308 for

antagonist activity
Ionized carboxylate correlated with c-terminal carboxylate of Ang II Imidazole ring correlated with imidazole side chain of His6 residue n-butyl group correlated with hydrocarbon side chain of Ile5 residue of Ang II

Ile5

N terminal

HIS6

Angiotensin II

C terminal

Benzyl group
The benzyl group of S-8308 was proposed to lie in the direction of the N-terminus of angiotensin II; however, it was not believed to have any significant receptor interactions.

Molecular modifications of S-8308

To improve - Receptor binding - Lipid solubility To assure adequate oral absorption

These changes resulted in the preparation of losartan (1995), a compound with high receptor affinity and oral activity.

Fig. The development of losartan from S-8308.

Some Angiotensin II Antagonists

Biphenyl analogs of Losatran

Losartan Valsartan Irbesartan Candesartan Telmesatran

Eprosartan
Eprosartan

Structure-Activity Relationships

Acidic groups
A: Carboxylic acid B: Phenyl tetrazole C: Phenyl carboxylate

Ile5 Asp1 His6

Tyr4

 The acidic group is thought to mimic either the Asp1 carboxylate or Tyr4 phenol of angiotensin II. In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho position for optimal activity. The tetrazole group is superior in terms ofMetabolic stability Lipophilicity and Oral bioavailability

 The n-butyl group of the model compound provides hydrophobic binding and, most likely, mimics the side chain of Ile5 of angiotensin II.

Losartan

 As seen with candesartan, telmisartan, and olmesartan, this n-butyl group can be replaced with either an ethyl ether or an npropyl group.

ethyl ether in place of n-butyl group

Candesartan (Bi-phenyl analogue)

n-propyl in place of n-butyl group

Telmesartan (Bi-phenyl analogue)

n-propyl in place of n-butyl group

Olmesartan (Bi-phenyl analogue)

 The imidazole ring or an isosteric equivalent is required to mimic the His6 side chain of angiotensin II.

Valine

Valsartan

Valsartan
The amide carbonyl of valsartan is isosteric with the imidazole nitrogen of losartan and can serve as a hydrogen bond acceptor similar to the imidazole nitrogen. Valsartan, named for the valine portion of the compound, is the first nonimidazolecontaining ARB and is slightly more potent than losartan.

R group
Carboxylic acid Hydroxymethyl group Ketone, or a Benzimidazole ring

R group
Interact with the AT1 receptor through either Ionic Ion-dipole or Dipole-dipole bonds