Med Chem Treatment of HTN: Renin Angiotensin System
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- What is the role of the kidney in the RAS?
- Kidney -> Pro-renin (peptide) -> Renin (protease)
- What catalyzes the conversion of Pro-renin to Renin?
- Cathepsin B
- What is the R.L.S. in the RAS?
- Angiotensinogen -> Angiotensin I cataylzed by Renin
- What is the role of chymase?
- Alternative, Non-ACE ANGII generating pathways
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What is the substrate for ACE?
What is the chemistry catalyzed by the enzyme?
What is the product of enzyme cleavage? -
Angiotensin I (a decapeptide)
Peptide Cleavage
Angiotensin II (a hexapeptide) - What is the correlation between ACE and bradykinin?
- ACE catalyzes the degradation of bradykinin (a stimulator of biosynthesis of endogenous vasodilators) to inactive fragments.
- What 4 pieces of additional information should be known about ACE?
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1)Limited substrate specificity (doesn't accept all decapeptides)
**REQUIRED - carboxylate anion to be present in substrate**
2)CArboxydipeptidase-cleaves starting at carboxy terminus 2 amino acids at a time
3)Exopeptidase-cleaves at the terminus of a peptide
4)Metalloprotease-contains a critical Zn++ ion in each active site - SAR of ACE Inhibitors
-
1)N-ring must contain COOH to mimic C-terminal carboxylate
2)A sulfahydryl group, carboxylate, or phosphinate can serve as Zn++ binding groups
3)Binding of Zn++ through either a carboxylate or phosphinate mimics peptide hydrolysis transition state
4)Large hydrophobic heterocyclic rings in the the N-ring increase potency and alter pharmaokinetic parameters - What should be known about sulfhydryl containing ACE inhibitors and compounds?
-
They produce high incidence of skin rash and taste disturbances
Can form disulfides which may shorten duration of action
Sulfhydryl group shows superior binding to zinc - What is a complication associated with ACE inhibitors?
- Non-productive cough (need to treat with a narcotic)
- What are the two active sites proposed to be present in ACE?
- Angiotensin I and Bradykinin
- How more endogenous substrates are there for ACE?
- More than 1
- What is a site selective inhibitor?
-
Inhibits only the conversion of ATI to ATII
No binding of these agents to bradykinin-related ACE active site - What is the good and bad news of a site selective inhibitor?
-
Good = No cough
Bad = Decreased effect due to absence of vasodilation component of mechanism - What is the chymase inhibitor?
- CP-162,213
-
ATII receptors subtype AT1:
What is its location?
What type of receptor is it?
What is its 2nd messenger?
What are the 4 physiological effects of receptor activation upon binding of ATII? -
1)Aorta, Liver, Adrenal Gland
2)G-protein coupled receptor-7 transmembrane domains
3)Phosphoinositol
4)a-Vasoconstriction
b-Aldosterone release
c-Catecholamine release
d-renal Na+ reabsorption -
ATII receptors subtype AT2:
What is its location?
What type of receptor is it?
What is its 2nd messenger?
What are the 4 physiological effects of receptor activation upon binding of ATII? -
1)Adrenal gland, uterus, brain
2)Several subtypes of AT2 binding site
3)None identified
4)a-renal function
b-Restinosis
c-Growth
d-wound healing - SAR for non-peptide based AT1 selective receptor antagonists
-
1)Position #1: Called "variable region"
-Biphenyl substituent or aromatic heterocycle can take the place of one of the phenyl rings
-In ortho position, there must be an acidic functional group (COOH, Sulfonamide, Tetrazole)
2)Position #2-"hydrocarbon region"
-3-4 carbons optimal, branching is bad, double bond is Okay
3)Position#3-Scaffolding ONLY-no interaction with the receptor
4)Position#4-EWG
-lipophilic in character
-I>Cl>Br
-F is Okay
5)Position#5-H-bonding region
-small and must be H-bond acceptor (COOH, CH2OH) - How do you increase potency in an AT1 selective receptor antagonist if the H-bonding region in postion #5 has the substituent CH2OH?
- Oxidation due CO2H