Pharmaceutical Chemistry of cardiovascular system drugs I

Question 1

Renin-angiotensin pathway
Angiotensinogen

Answer 1

• Regulate blood volume and electrolytes
• Formed by 452 amino acids
• N- terminal 12 amino acids

Question 2

What does Renin do?

Answer 2

• In angiotensinogen at the N-terminus the renin cuts between Leu and Val bond
• formation of 10 chain amino acid Angiotensin I

Question 3

What does Angiotensin converting enzyme do?

Answer 3

• Break between Phe and His to formation 8 chain amino acid form Angiotensin II
• This is a potent vasoconstrictor
• Increase peripheral resistance
• Rapid repressor response

Question 4

ACE mechanism

Answer 4

• Block synthesis of Angiotensin II inhibit ACE
• Zinc containing exopeptidase break terminal peptide chain
• form ionic bond with carboxylic acid of Leu and protonated amine of ACE
• Zn2+ binds to Phe at peptide bond
• Additional binding at Phe and Leu
• bond Hydrogen on His
• Cut peptide bond Phe and His hydrolysis

Question 5

Captopril

Answer 5

• Similar interaction to angiotensin I
• ZN2+ bind to SH
• Ionic bonding with carboxylic acid and protonated amine
• Carbonyl group hydrogen bonding

Question 6

Enalaprilat

Answer 6

• Has carboxylic acid ionic bond with 3HN+-ACE
• Zn2+ interaction with carboxylic acid

Question 7

Side effects of Captopril

Answer 7

• Causes severe skin rashes
• Taste disturbance

Question 8

Enalaprilat

Answer 8

• Zwitterion at physiological pH
• Nitrogen very basic becomes protonated positive charge
• Carboxylic will have negative charge at pH (6-7)
• Low bioavailabity and cannot give orally
• Zinc double interaction with carboxylic acid

Question 9

Enalapril

Answer 9

• Instead of the carboxylic acid use of ester
• Neutral charge of NH increase bioavalability when in the intestine as it is an ester
• Less effective than enalaprilat as an ACE inhibitor
• In-vivo changes from enalapril to enalaprilat as it is a prodrug

Question 10

Ramipril

Answer 10

• Carboxylic acid to mimic C terminus of angiotensin I
• Large hydrophobic and hydrophobic heterocyclic rings
• Zinc binding group (SH) (COOH) -SH good binding but bad taste and skin rash
• Mimic Phe hydrolysis transition state
• Esterification bioavailability as a prodrug
• Always methyl group
• Stereochemistry must be consistent with L-amino acid

Question 11

Angiotensin II receptor blockers

Answer 11

• AT1: Brain, neural, renal, adrenal and myocardial tissue
• 1,000 fold more blocking with AT1 than AT2

Question 12

Losartan

Answer 12

• S-8308 weak antagonist mimic weak substrate to improve AT1 receptor binding

Question 13

Structure of losartan

Answer 13

• TRY4 Phenol or Asp1 COO of the angiotensin II
• Tetrazole and COOH must be in ortho position for optimal activity
• N-butyl group for hydrophobic binding
  -Imidazole ring and different R groups

Question 14

Calcium channel blockers

Answer 14

• Increase the amount of Calcium in the inner part of the cell between actin and myosin
• Influx is regulated by operating channels Na/Ca2+ leak pathways

Question 15

Function of Calcium Channel blocker

Answer 15

• Block Ca2+ influx by binding on allosteric site

Question 16

Essential component for activity of CCB

Answer 16

• 1,4-Dihydropyradine is essential
• Substituted phenyl ring at C4 optimise activity
• Substituents x must be ortho or meta locking active conformation essential for activity
• Ester groups at C3 and C5 are non identical
• Decreasing antagonist may have an agonist as electron withdrawing

Question 17

1,4-dihydropyridine

Answer 17

• Active Nifedipine 1,4-DHPs becomes oxidized to pyridine to become inactive
• Use no grapefruit juice inhibit the activity of CYP450 stop metabolism so high conc

Question 18

Diuretics

Answer 18

• Increase urine formation increase excretion of electrolytes
• Treatment of odema

Question 19

Thiazide like diuretics

Answer 19

• Compete for Cl- binding site of Na+/Cl- symporters inhibit reabsorption

Question 20

Mineralocorticoid receptor Antagonist

Answer 20

• Aldosterone potent mineral corticoid from adrenal cortex

Question 21

Spironolactone

Answer 21

• Competitively inhibits aldosterone interfere with reabsorption of Na+ and Cl-
• Gamma-lactone ring important for PK
• Methionine residue in MR
• Oral administer 90% absorbed

Question 22

Carenone

Answer 22

• Antagonist of aldosterone prodrug

Question 23

HMG-CoA reductase

Answer 23

• Enzymes that catalyzes the 3rd step from acetyal-CoA to Mevalonic acid
• Thioester to primary alcohol

Question 24

Cholesterol

Answer 24

• Component of all cell membranes
• Precursor for androgens and oestrogens, progesterone and adrenocorticoid

Question 25

HMG-CoA reductase inhibitors

Answer 25

- Natural product and synthetic agent Statins - Similar effects on plasma cholesterol levels but different PK profile and potency

Question 26

Function of HMG-CoA reductase inhibitors

Answer 26

- Inhibit cholesterol biosynthesis - Satin in the presence of the binding site in HMG-CoA reductase then HMG-CoA cannot bind

Question 27

First ever statins

Answer 27

- Mevastatin and Lovastatin first statin - fungal metabolites 10,000 fold better affinity than natural enzyme

Question 28

Intermediate formation between conversion

Answer 28

- In the inactive prodrug the lactone ring in-vivo is hydrolyzed to open ring formation mimic tetrahedral intermediate - Bicyclic portion mimics binding of CoA

Question 29

2 families of SAR of HMG-CoA similarity simvastatin and atorvastatin

Answer 29

- Both have 3,5-dihydrocarboxylate which is essential for inhibitory activity - 2.5-3.5 Ionized at physiological pH - Absolute stereochemistry of OH in 3 & 5 must be R - C=C to increase or decrease activity and 2 carbon essential between C5 and ring

Question 30

Differences between the two families simvastatin has

Answer 30

- Bicyclic ring essential for anchoring the compound to enzymes active site - R2 = CH3 a more potent compound - R3 = OH a more hydrophilic compound

Question 31

Differences between two families Atorvastatin