Antihypertensive Agents (Medicinal Chemistry)

thiazides

warning for sulfonamide hypersensitivity reactions (nausea, allergy, hematopoietic disease

benzothiadizine

Thiazides derived from ___________ which are bicyclic heterocyclic benzenes.

lipophilicity and duration of action

What do the alkyl groups on position 2 on thiazides increase?

increase potency

What does the lipophilic groups on the position 3 of the thiazides do?

increases activity 10 fold

What does the lipophilic groups on the position 3-4 of the thiazides do?

chlorine

What is the electron withdrawing group on the position 6 of thiazides?

sulfonamide

The _________ on position 7 adds activity (hyper-sensitivity) to thiazides.

Chlorothiazide

-Representative thiazide diuretic.

-It was patented in 1956 and approved for medical use in 1958.

-Warning: sulfonamide sensitivity!

Hydrochlorothiazide

-Widely used thiazide diuretic.

-Prototypical thiazide.• 3-4 bond saturated => more active than chlorothiazide.

-Called HCTZ.

-Warning: sulfonamide sensitivity!

phthalimide ring

Chlorthalidone has a structural modification which is the __________

Indapamide

-Structure: 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline.

-Displays a chlorobenzenesulfonamide.

-No benzothiadiazine scaffold.

-Longer activity and inhibits carbonic anhydrase.

-Warning: sulfonamide sensitivity!

"sulfa" allergy

-3-6% of the population

-sulfonilamide (sulfone + amide)

sulfonamide

is a synthetic derivative of p-aminobenzenesulfonamide,which is sulfonilamide in antibiotics like sulfamethoxazole (SMX)

potassium-sparing diuretics

-Reduce urinary excretion of K+.

-May cause hyperkalemia at different levels.

-Combination with the other diuretics to maintain the [K+] balance.

-May not have a clinically significant effect on BP

Spironolactone

-Cyclized (lactone) aldosterone (steroid hormone) derivative

-Competitive antagonist against aldosterone

-Selective aldosterone receptor blocker

-Old and widely used drug

Eplerenone

-Cyclized aldosterone (steroid hormone) derivative

-Structurally similar to Spironolactone (small chemical modifications)

-Competitive antagonist against aldosterone

-Selective aldosterone receptor blocker

-Widely used potassium-sparing diuretic

triamterene

-Sodium channel blocker

-Three highly aminated aromatic rings

-Bicyclic ring (pyrimidine and pyrazine)

-Weak potency

Amiloride

-Sodium channel blocker

-Open-ring analog of triamterene (chlorination instead of phenyl)

-100-fold more potent than triamterene

propranolol

s a racemic mixture of 2 enantiomers where the S(-)-enantiomer has approximately 100 times the binding affinity for beta adrenergic receptors

Metoprolol

-Selective blocker of the β1-adrenergic receptors in the heart.

-Chemically similar to propranolol, but with a hydroxyethyl group attached to the C4 carbon of a phenol group instead of a naphthalene(1-naphthol)

Verapamil

As a phenylbutylamine, this compound

contains a phenylbutylamine moiety,

which consists of a phenyl group

substituted at the fourth carbon by a

butan-1-amine

Dilitiazem

As a benzothiazepine, it contains a benzene fused to a thiazepine ring (a seven-membered ring with a nitrogen atom and a sulfur atom replacing two carbon atoms)

Nifedipine

As a dihydropyridinecarboxylic acid, it contains a

dihydropyridine moiety bearing

carboxylic acid groups

ACEis

Inhibit, directly or indirectly, the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II,

consequently decreasing inactivation of bradykinin (a potent

vasodilator)

Captopril

-Competitive inhibitor of ACE.

-Sulfhydryl-containing analog of proline.

-Sulfhydryl moiety enables ACE inhibition

Enalapril

-Prodrug which is converted by hydrolysisof the ethyl ester to enalaprilat, the activeACE inhibitor form with carboxylic acid.

- (S)-(-)-1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-L-proline. Modifieddipeptide containing Ala and Pro

prodrug

Enalapril

active form

Enalaprilat

Perindopril

-ACE inhibitor

-As a prodrug, its ester group is cleaved in the liver and converted into its carboxylic acidactive form Perindoprilat

-Non-sulfhydryl proline-containing dipeptide

prodrug

Perindopril

active form

Perindoprilat

Ramipril

-ACE inhibitor.

-As a prodrug, its ester group is cleaved in the liver, and to a lesser extent in the kidneys,

and converted into its carboxylic acid active form Ramiprilat.

-Non-sulfhydryl proline-containing dipeptide

prodrug

Ramipril

active form

Ramiprilat

Trandolapril

-ACE inhibitor.

-As a prodrug, its ester group is modified in the liver, to its biomedically active its carboxylic

acid active form, Trandolaprilat.

-Non-sulfhydryl Proline-containing dipeptide

prodrug

Trandolapril

active form

Trandolaprilat

Fosinopril

-ACE inhibitor.

-Phospho ester-containing prodrug that is rapidly

hydrolyzed in the gastrointestinal mucosa and liver to

Fosinoprilat (phosphonic acid active form).

-Analog of proline

prodrug

Fosinopril

active form

fosinoprilat

benazepril

-ACE inhibitor.

-As a prodrug, its ester group is cleaved in the

liver and converted into its carboxylic acid

active form Benazeprilat.

-Non-sulfhydryl and benzazepine

prodrug

benazepril hydrochloride

active form

benaeprilat

quinapril

-ACE inhibitor.

-As a prodrug, its ester group is cleaved in the liver and converted into its carboxylic acid

active form Quinaprilat.

-Non-sulfhydryl and quinolone

prodrug

quinapril

active form

quinaprilat

moexipril

-ACE inhibitor.

-Ester-containing prodrug that is rapidly hydrolyzed in the gastrointestinal mucosa and liver

to Moexiprilat (carboxylic acid active form).

-Non-sulfhydryl and di-O-methyl quinolone

prodrug

Moexipril

active form

Moexiprilat

sulfhydryl

can cause taste disturbances and maybe skin rashes

captopril

is preferable in patients with underlying liver issues

Dicarboxylic

_______ ACEis are more potent than captopril

no

Does captopril have activation?

benzazepine

What is the scaffold of benazepril?

quinolone

What is the scaffold of quinapril?

methylated quinolone

What is the scaffold of moexipril?

sulfhydryl + carboxylic

What are the functional groups of captopril?

phosphonic + carboxylic

What are the functional groups of fosinopril?

ARBs

-sartan

-Bind and block angiotensin II receptor

-similar benefits of ACEis, but with no action on bradykinin metabolism and are more selective blockers of angiotensin effects that ACEis

losartan

-As a biphenyl, this organic compound contains benzene rings linked together by a C-C bond.

-was granted FDA approval on 14 April 1995

-First marketed blocker of angiotensin II type 1 (AT1)