L25 Medicinal Chemisty of Antihypertensives

The drugs that are Angiotensin II ‘blockers’ are thought to be AT1R antagonists.

Peptides are usually very specific and have [blank_start]high[blank_end] affinity for the target, but have [blank_start]poor[blank_end] chemical and biological stability, and so a [blank_start]short[blank_end] half life. They also have [blank_start]poor[blank_end] oral bioavailability.

Captopril was the first orally available ACE inhibitor. It was well known to cause taste disturbances. It contains a [blank_start]proline[blank_end] amino acid, and has two S [blank_start]stereocentres[blank_end], the same stereochemistry as the endogenous peptide. It contains a thiol because ACE is a zinc metalloenzyme, and the thiol group [blank_start]chelates[blank_end] very well to zinc. Multiple daily [blank_start]dosing[blank_end] requirements and side effects due to thiol drove further drug discovery.

Enalaprilat was made when the sulfhydryl part of captopril was replaced with something else that fits well into the ACE ligand [blank_start]binding[blank_end] site and can chelate to a [blank_start]zinc[blank_end] ion. Enalaprilat is 10-fold more [blank_start]potent[blank_end] than captopril. To overcome the [blank_start]poor[blank_end] oral bioavailability of enalaprilat, the prodrug enalapril was made. Enalaprilat is converted by [blank_start]esterases[blank_end] (mostly in the liver) to enalaprilat.

Most other carboxylate-based ACE inhibitors (e.g Cilazapril, perindopril, quinapril) also are prodrugs that have an ester which is hydrolysed to the active drug.

Using the endogenous ligand angiotensin as the structural starting point, angiotensin II receptor blockers were made. They are [blank_start]small molecules[blank_end] with similar key ligand-receptor contacts. They [blank_start]compete[blank_end] with angiotensin II and blocks it’s action. An example is [blank_start]losartan[blank_end]. An analogue prodrug of this is [blank_start]candesartan[blank_end] cilexetil. It is activated by [blank_start]ester[blank_end] hydrolysis which occurs during [blank_start]absorption[blank_end] from the GI tract. It is long [blank_start]acting[blank_end] –because of [blank_start]tight[blank_end] binding to AT1R and [blank_start]slow[blank_end] dissociation from the receptor.

Calcium channel blockers act at L-type [blank_start]voltage[blank_end]-gated calcium channels. L-type are [blank_start]long[blank_end]-lasting, and large, and located in skeletal, cardiac and smooth muscle. The blockers [blank_start]bind[blank_end] to the α1 subunit. Most calcium channel blockers are dihydropyridines which have: - [blank_start]Phenyl ring[blank_end] at C4 - [blank_start]Esters[blank_end] at C3 and C5 - [blank_start]Electron withdrawing[blank_end] group Those funded in NZ are amlodipine, felodipine, isradipine, nifedipine, and nimodipine. All racemic except nifedapine.

Drugs that block the binding of adrenalin and noradrenalin to the adrenoceptors and do not act as agonists are AR blockers. - ‘First generation’ ARBs are non selective, acting on [blank_start]beta[blank_end] adrenoceptors, designed via [blank_start]chain[blank_end] extension of the endogenous agonist catecholamines. The catechol is [blank_start]replaced[blank_end] with an extended structure to reduce COMT metabolism. There is a [blank_start]linker/spacer[blank_end] added between the Ar and alcohol. A short length [blank_start]bulky[blank_end] group is added to the amine. An example is propanolol. - The 'second generation’ are [blank_start]selective[blank_end] for β1AR. All have functional groups off the phenyl ring, capable of [blank_start]hydrogen[blank_end] bonding. An example is metoprolol. - There are also α1-AR blockers indicated for hypertension, like prazosin. They have an [blank_start]extended[blank_end] chain with an [blank_start]Ar[blank_end] group.

Thiazide diuretics block the Na+Cl- symporter, disallowing Na+ reabsorption and increasing urine output. They also cause arteriolar vasodilation. Structural requirements of the drugs: - [blank_start]electron withdrawing[blank_end] group at C-6 (ie Cl, CF3) - C-7 must be [blank_start]sulfonamide[blank_end] - C-3 [blank_start]lipophilic[blank_end] group, to increase in potency and duration of action (ie benzyl)

Loop diuretics inhibit NKCC2 (the [blank_start]luminal[blank_end] Na/K/2Cl co-transporter) and cause a strong diuresis. They are meta-substituted sulfamoylbenzoic acids, meaning there is a [blank_start]sulfamoyl or sulfonamide[blank_end] group on one meta position of a ring and a [blank_start]benzoic[blank_end] acid on the opposite meta position. Note: [blank_start]Bumetanide[blank_end] is more potent than [blank_start]furosemide[blank_end].