Lecture 2 medchem

What part of the RAS system causes hypertension

Abnormalities causing release of renin and overproduction of angiotensin II

How does ACE contribute to hypertension

Causes vasoconstriction and inactivates vasodilator bradykinin leading to hypertension

What does ACE cleave

In between Phe8 and His9

What does Angiotensin 1-7 do

Vasodilation

What are the 3 targets for antihypertensive drugs

ACE

Renin 

AT1 antagonist

What type of peptide is Angiotensin 2

Octapeptide

What does ACE rewuire to recognize a substrate

The tripeptide bond Phe8-His9-Leu10

What are the types of Zinc chelating groups

Sulfhydril

Carboxylate containing

Phosphinate containing

Which zinc chelating groups are transition state mimetics

Phosphinate and Carboxylate

What is the first ACE inhibitor

Captopril 

What binds to S2 in Captopril

Proline

What creates ionic bond in Captopril

Lys 511

What are the inactive metabolites of Captopril

Disulfide Dimer

Captopril-cysteine disulfide 

What are the disadvantages of Captopril

Skin rashes

loss of taste

Short duration of action

Which class of ace inhibitors were created as a result of Captopril side effects

Dicarboxylate class

What type of drug is Enalapril

Prodrug that is oral 

What makes Enalapril a transition state mimetic

Tetrahedral carbon

What structural change led to the discovery of Enalapril

Phenylethyl group on R4

What is the active form of Enalapril

Enalaprilat 

What is the active form of Ramipril

Ramiprilat

What is a unique SAR of Ramipril

C terminal pro ring expansion to enhance lipophilicity to acheive deep binding in the S2 pocker of ACE active site

What does Lisinopril have a greater affinity for ACE compared to 

Enalaprilat

What side chains bind to S1 for Lisinopril

Lys side chain

What tripeptide is Lisinopril a derivative of

Phe-Lys-Pro

Does Lisiniopril require biactivation

No 

What is a unique side chain of Fosinopril

Phenylbutyl

Which drug needs to become hydrolyzed to become active

Fosinopril

What is the active drug for Fosinopril

Fosinoprilat 

What compensates for weaker zinc chelating property of phosphinate

Additional hydrophobic phenylbutyl moiety interactions

Within the carboxylate series when X is n-butylamine what does it mean

Not require prodrug for oral activity

What must N ring contain in ACE inhibitors 

Carboxylic acid to mimic C-terminal carboxylate of ACE substrate

Which ace inhibitors are acidic

Captopril

Fosinopril

Are al ACE inhibitors L-proline derivatives

False

Which 2 ace inhibitors are not prodrugs

Captopril 

Lisinopril 

What is a prominent side effect of ACE inhibitors

Dry cough because of lack of specifity of drugs

Is Losartan peptide or nonpeptide

Non peptide

What is the structure of ARBS made of 

A;iphatic chain and an acidic group

What does Acidic group mimic for ARBs

Asp1

What does phenolic OH in ARBs mimic

Tyr4

What is the active metabolite of Losartan

EXP-3174

Explain the structure of Valsartan

Nonheterocyclic with a acetylated amino acid 

What is the structure of Irbesartan

Imidazolinone ring with carbonyl group that is H bond acceptor and spirocyclopentane ring

Structure of Telmisartan

Benzimidazole

What is the structure of Eprosartan

Lacks biphenyl carboxylix acid and unusual Imidiazole for C5

Which ARBs are prodrugs

Olemsartan

Azilsartan

Candesartan

Which drug is a renin inhibitor

Aliskerin

What does Renin cleave to make angiotensin

between Leu 10 and Val 11

What does Alkiserin inhibit

The formation of Angiotensin 1 and 2

What is an advantage of Alkiserin

Does not cause increase of renin

Which amine of Aliskiren is basic 

On the 4 position

Is Alkisaren peptide or non peptide

Non peptide

What is the structure of selective alpha 1 antagonists

Quinazoline derivatives with substituted piperazine ring

What is the MOA of alpha 1 antagonists

Inhibits a1 adreno receptors 

Leads to vasodilation 

Examples of a1 antagonists

prazosin

Terazosin

Doxazosin

What do Central a2 Adrenergic agonists do

Reduce sympathetic outflow to cardiovascular system creating hypotensive effect

What is the pharmacophore of Central a2 adrenergic agonists

Phenylimino imidazole 

Unionized to cross CNS 

Leads to negative feedback to create vasodilation

Which drug is a2 adrenergic agonist

Methyldopa pro drug converted to methyl-norepinpherine