Angiotensin 2 Receptor Blockers (ARB)s And Renin Inhibitors

Question 1

How does changing carboxylic acid to tetrazol affects the characteristics of the drug?

Answer 1

It gives it a lower bioavailability, makes it ionizable, increases passive diffusion, and makes it highly polar

Question 2

Angiotensin 2 receptor blocker

Answer 2

-four subtypes AT1 to AT4 : AT1 causes vasoconstriction in adrenal cortex ( preventing cortisol secretion) and blood vessels (prevents blood flow)
- selective AT1 antagonist known as sartans ( first was losartan)

Question 3

Losartan ( selective AT1 antagonist)

Answer 3

-derived from a biphenyl structure that has a good antihypertensive activity but has to be injected due to poor oral absorption
- solved problem by replacing the polar carboxylic acid with a less polar tetrazole ring (bioisosteric replacement)
-losartan undergoes oxidative metabolism to form EXP3174 which is a more potent antagonist

Question 4

three key features in EXP3174 for good antagonist activity:

Answer 4

1-Strong binding is associated with the acidic tetrazole ring and a hydrophobic substituent on the imidazole ring.
2-carboxylic acid, which is ionized under physiological
conditions.

Question 5

It is thought that the carboxylate group forms an———- interaction with a ———— to produce an induced fit that forces the receptor into an ———.

Answer 5

ionic, lysine residue

inactive conformation

Question 6

The ————- mainly serve as a scaffold to orientate the three key binding groups, allowing them to —————— in the binding site.

Answer 6

imidazole and biphenyl rings.

interact simultaneously with complementary binding regions.

Question 7

List the inverse agonist sartans;

Answer 7

Candesartan, olmesartan,and valsartan

Question 8

All sartans contain:

Answer 8

1-hydrophobic substituents
2-two acidic groups like tetrazole (except irbesartan) for good binding and activity
3- example: azilsartan contains an oxadiazole ring. The binding affinity is weaker than candesartan, it’s in Vivo activity and is superior due to increased bioavailability

Question 9

Valsartan

Answer 9

-named after valine portion of the compound (nonimidazole- containing ARB) and is more potent than losartan
-the amide carbonyl of valsartan is isosteric with imidazole nitrogen of losartan and can serve as a hydrogen bond acceptor similar to imidazole nitrogen

Question 10

Irbesartan (ARB)s

Answer 10

-spiro compound (spirocyclopentane can provide enhanced hydrophobic binding)

Question 11

Where do you find a Benz imidazole ring and how does it affect the binding?

Answer 11

-Azilsartan, Candesartan, and telmisartan.
-It enhances hydrophobic binding, similar to that seen with the spirocyclopentane ring of benzimidazole ring.
-Valsartan and Eprosartan are exceptions that contain ONLY ONE of the above features

Question 12

What causes a poor oral absorption?

Answer 12

The presence of 2 acidic groups in sartans
SO extended esters (double esters) have been designed.

Question 13

What observation was made on simple methyl or ethyl esters?

Answer 13

They were found unsuitable as prodrugs for sartans as they are poor substrates for the body’s esterase enzymes due to steric issues (extended esters are used instead).

Question 14

Why are ARBs alternatives to ACE inhibitors?

Answer 14

-They block AT1 receptors decreasing its activation by angiotensin 2.

Question 15

How are ARBs similar in pharmacological effects to ACE inhibitors?

Answer 15

• Both produce arteriolar and venous dilation and block aldosterone secretion (lowering blood pressure and decreasing salt and water retention)
  -similar adverse effects but risks of cough and angioedema are significantly decreased.

Question 16

How do ARBs affect bradykinin levels?

Answer 16

They do not increase bradykinin levels (not peptidases)
ACE have more side effects as ARB are more selective and cause no resistance.

Question 17

Renin Inhibitors

Answer 17

1-block synthesis of angiotensin 1 and will lower angiotensin 2 levels

Question 18

What are the advantages in targeting renin?

Answer 18

1-first enzyme in RAAS cascade and catalyzes the rate-limiting step for the process making them more efficient than inhibiting ACE.
2-blocking renin avoids build up of angiotensin 1 that results from inhibiting ACE
3-Renin only accepts angiotensinogen as a substrate and appears to have no other biochemical role. Therefore, enzyme inhibitors showing selectivity for Renin should only affect RAAS cascade but not other biochemical processes minimizing side effects

Question 19

Aliskiren

Answer 19

-Transition state isoistere that mimics tetrahedral transition state of enzyme catalysed reaction and enhances binding affinity.

Question 20

Transition state isoisteres

Answer 20

-bound more strongly than either the substrate or the product so it makes sense to design drugs based on the structure of the transition state rather than substrate or the product
-inherently unstable and moieties are used to mimic the crucial features of transition state,but are stable to the enzyme catalyzed reactions

Question 21

Transition state of amide hydrolysis

Answer 21

-Is thought to resemble the tetrahedral reaction intermediate
-geminal diol is inherently unstable
-hydroxethylene moiety is a transition state isoistere as it shares same tetrahedral geometry, retains one of the hydroxyl groups and is stable to hydrolysis.