W2 Pharmaceutical Chemistry of cardiovascular drugs

Question 1

What are the agents affecting the Renin-Angiotensin Pathway? (5)

Answer 1

• ACEi and ARB
• Calcium Channel Blockers (CCB)
• Thiazide-like diuretics
• Alpha and beta blockers
• Mineralocorticoid Receptor Antagonists

Question 2

The Renin-Angiotensin pathway:

What is the role of Renin?
What is the role of ACE?

Answer 2

Renin cuts the Leu-Val bond in Angiotensinogen (a protein made up of a.a) to form Angiotensin l (a peptide of 10 a.a.)

ACE cuts the bond between Phe-His
Converts Angiotensin l to ll

Question 3

What is the role of ACEi?

Answer 3

Block synthesis of Angiotensin II by inhibiting ACE (Enzyme Inhibitors)

Zinc-containing exopeptidase (breaks the terminal peptide bond in a peptide chain)

Question 4

What is Angiotensin ll?
What happens if the body produces excess angiotensin ll? (3)

Answer 4

• A potent vasoconstrictor
• Increases peripheral resistance
• rapid pressor response
• Hypertension, contributes to CVD disorders

Question 5

What are the steps in the chemical mechanism of ACE?

Answer 5

1. Ionic bond
2. Interaction with the labile peptide bond
3. Additional binding
4. H-bond

Question 6

What type of drug was captopril?
How is it adapted for its function?
What are its two common side effects?

Answer 6

• The first ACEi on the market
• SH (sulfhydryl): enhanced affinity for the zinc, excellent inhibitory activity

Skin rashes and taste disturbances (e.g.,
metallic taste and loss of taste)

Question 7

What type of drug is Enalapril?
Is enalaprilat more potent?

Answer 7

ACEi
It is a pro-drug that is converted into Enalaprilat by going from carboxylic acid COOH to Ester COOC

10-fold more potent: chelate zinc, mimic transition state of angiotensin I, phenyl group mimic Phe, excellent IV activity (only marked for IV)

BUT it is a Zwitterion at physiological pH

Question 8

ACE inhibitors: Enalapril and other dicarboxylates
What are their properties?

Answer 8

• Pyrrolidine ring (Enalapril)
• Larger bicyclic, spiro ring systems or hydrophobic systems attached to pyrrolidine
• Hydrophobic pocket: increase
  binding and potency
• Influence PK properties

Question 9

Structure-Activity Relationship of ACEi

Answer 9

A. N-ring must contain COOH to mimic the C-terminal COOH of Angiotensin I
B. Large hydrophobic heterocyclic rings (i.e., the N-ring) increase potency/PK
C. Zinc binding groups: SH (Captopril), COOH (Ramipril), or POOH (Fosinopril).
SH group shows superior binding to zinc but skin rash and taste→disturbances
D. Mimic the Phe. Mimic the peptide hydrolysis transition state. Compensates for lack of a SH
E. Esterification of COOH or POOH produces an orally bioavailable prodrug
F. X is usually methyl
G. Stereochemistry needs to be consistent with L-amino acids (natural)

Question 10

ACE inhibitors: more info

Answer 10

A. Captopril (SH) and fosinopril (POOH) are acidic drugs, but all other ACEi are amphoteric (can act as either an acid or a base)

pK a = 8.02 if R 2= H (N ionised (NH 2+ ) at physiologic pH
pK a = 5.49 if R 2= Alkyl (N is un-ionised (NH) at physiologic pH

pKa = 2.5-3.5, ionised (COO - ) at physiologic pH

B. All possess good lipid solubility (large hydrophobic heterocyclic rings attached to pyrrolidine), except of captopril, enalaprilat, and lisinopril (only pyrrolidine)
C. Lisinopril and enalaprilat are excreted unchanged. All other ACEi undergo some degree of metabolic transformation (based on their structural features: e.g. Glucuronide conjugation to the COOH)
D. Compound ending in -PRIL

Question 11

Angiotensin II receptor blockers (ARB):
What are the types?

Answer 11

AT1: brain, neuronal, vascular, renal, hepatic, adrenal, and myocardial tissues.
Mediate the cardiovascular, renal, and CNS effects of angiotensin Il

AT2: mediate a variety of growth, development, and differentiation processes

10,000-fold more selective for the AT 1 .
Competitive antagonists of angiotensin II at its binding site and prevent/reverse
all of its known effects
AT 2 : mediate a variety of growth, development, and differentiation processes

ARBs: 10,000-fold more selective for the AT 1.
-Competitive antagonists of angiotensin II at its binding site and prevent/reverse
all of its known effects

BUT non-stimulation of AT 2 receptor in conjunction with AT 1 receptor
antagonism: may cause long-term adverse effects → compounds that exhibit balanced antagonism at both receptors are preferred

Question 12

Structure-Activity Relationship of ARB (sartans)

Answer 12

A. Acidic group: mimics either Tyr4 phenol or Asp1 COO of
angiotensin II. Include: COOH (), phenyl tetrazole ()
(losartan) or isostere, or phenyl carboxylate ()
B. Biphenyl series: tetrazole (*) and COOH (**) must be in ortho
position for optimal activity. Tetrazole: superior metabolic
stability, lipophilicity, and oral bioavailability
C. n-butyl group: hydrophobic binding. Mimics side chain Ile5
D. Imidazole ring or an isosteric equivalent: mimic His6
E. R: different groups (-CH2COOH, -CH2OH, ketone, etc.), ionic, ion–
dipole, or dipole–dipole bonds with AT1 mimic interaction of Phe8

Question 13

ARBs : more info

Answer 13

All ARBs are acidic drugs

• pK a = 6: 90% ionised (N - ) at
  physiologic pH (e.g. Losartan, valsartan, etc,)
• pK a = 3-4 ionised (COO - ) at
  physiologic pH (e.g. telmisartan, etc,)

B. Not excellent lipid solubility. Tetrazole →more lipophilic, the 4 N create a
greater charge distribution → enhanced binding and bioavailability
C. 14% of a dose of losartan: oxidised by
CYP2C9 and CYP3A4 to EXP-3174, a non-
competitive AT 1 antagonist that is 10- to
40-fold more potent. CV effects seen
result from the combined actions
D. All other ARBs: excreted
unchanged (80%).

Question 14

Calcium Channel Blockers (CCBs)
-FOR INFO

Answer 14

Calcium: key component of the excitation-contraction coupling process on CVS
Cellular messenger to link internal or external excitation with cellular response
↑ [Ca 2+ ] cytosolic → binding Ca 2+ to regulatory proteins → interactions between
actin and myosin → muscle contraction. Reversible process

Regulation of cytosolic [Ca2+ ]: influx, efflux, and sequestering mechanisms
Influx: receptor-operated channels, Na+ /Ca2+ exchange process, “leak” pathways,
and potential-dependent channels

Efflux: adenosine triphosphate–driven membrane pump, Na + /Ca2+ exchange process
Inhibition of Ca2+ flow through potential-dependent channels: vasodilation and
decreased cellular response to contractile stimuli

Calcium Channel Blockers: interaction with potential-dependent channels, treatment of hypertension and ischemic heart disease

Question 15

Calcium Channel Blockers (CCBs)
- How do they work?

What are some examples?

Answer 15

Block Ca2+ influx, BUT do not simply “plug the hole” and physically block the Ca2+
potential-dependent channel →they exert their effects by binding to specific and
different receptor allosteric sites

1,4-Dyhydropyridines -Nifedipine
Benzothiazepines- Diltiazem
Phenylalkylamines- Verapamil
Diaminopropanol ethers- Bepridil

Question 16

SAR of 1,4-dihydropyridine

Answer 16

A. 1,4-dihydropyridine ring: essential
B. Substituted phenyl ring at C 4 : optimise activity
C. Substituent X: need to be in ortho or meta. Lock active
conformation essential for the activity
D. Ester groups at the C 3 and C 5 positions optimise activity.
Other EWG: decreased antagonist activity. May have agonist activity
E. If esters at C 3 and C 5 are non-identical: C 4 is chiral→ stereoselectivity between the enantiomers is observed (selectivity for specific blood vessels). Marked as racemic
E. All (exception of amlodipine) have C 2 and C 6 = CH 3 .
Enhanced potency of amlodipine : 1,4-DHP receptor can tolerate
larger substituents at this position and that enhanced activity can be
obtained

Question 17

1,4-dihydropyridine (Nifedipine) ; more info
What are they metabolised by??
What is not recommended with these medicines and why?

Answer 17

1,4-DHPs are oxidatively metabolised to a variety of inactive compounds by CYP3A4

1,4-Dihydropyridine ring Converts into a Pyridine ring by CYP3A4

Coadministration of 1,4-DHPs with grapefruit juice: increase systemic concentration of the 1,4-DHPs. Due to inhibition of intestinal CYP450 by flavonoids and furanocoumarins specifically found in grapefruit juice
Compound ending in -PIDINE

Question 18

Diuretics
What are their functions? (3)

Answer 18

1. Increase the rate of urine formation targeting the kidney
2. Increased excretion of electrolytes (especially Na+ and Cl-) and water without affecting protein, vitamin, glucose, or amino acid reabsorption
3. Treatment of oedema (excessive extracellular fluid) (e.g., congestive heart
   failure) and in the management of hypertension

Question 19

What are diuretics often used to treat?

Answer 19

• Treatment of oedema (excessive extracellular fluid) (e.g., congestive heart
  failure) and in the management of hypertension

Question 20

What are the classes of diuretics? (4)

Answer 20

• Chemical class (thiazides and thiazides-like)
• Mechanism of action (carbonic anhydrase inhibitors and osmotic)
• Site of action (loop diuretics)
• Effects on urine contents (potassium-sparing/ potassium diuretics)

Question 21

What is different efficacy? (for info)

Answer 21

Ability to increase the rate of urine formation, e.g increase the excretion of Na+ filtered at the glomerulus ) and different site of action within the nephron

Question 22

Thiazide-like Diuretics

Mechanism of action/therapeutic activities

Answer 22

MoA= Acting on distal convoluted tubule: compete for Cl - binding site of the Na+/ Cl– symporter inhibiting reabsorption of Na + and Cl -

• Rapidly and completely
  absorbed from GI. Duration of action of up to 8 weeks.
• Extensive binding to carbonic anhydrase in the erythrocytes
• Quinazoline derivatives
  (metolazone and quinethazone)
• Phthalimide derivatives (chlorthalidone)
• Indolines derivatives (indapamide)

Question 23

Mineralocorticoid Receptor Antagonist
e.g. Spironoloactone

Answer 23

Aldosterone: potent mineralocorticoid secretes from adrenal cortex

Binds mineralocorticoid receptor (MR) →promotes salt (NaCl) and water retention and potassium and hydrogen ion excretion

Substance antagonising effects of aldosterone: Good diuretic drug
Spironolactone and eplerenone are antagonists (potassium- sparing diuretics)

Question 24

Spironolactone

Answer 24

Competitively inhibits aldosterone binding to the MR → interfering with reabsorption of Na + and Cl - ions and water in the kidney

Aldosterone: C-7–unsubstituted→ interaction with a methionine residue in the MR ligand binding domain
→Receptor activation and subsequent transcription. Interaction sterically hindered by C-7 substituent, thereby leaving MR in an inactive conformation.

• Oral administration, approximately 90% is absorbed
  Significantly metabolised during its first passage through the liver to its major
  active metabolite, canrenone
  Canrenone: active form of spironolactone (prodrug) as an aldosterone antagonist.
• Formation of canrenone, cannot fully account for the total activity of spironolacton

Question 25

Hyperlipidaemia:
What drugs can be used to treat it? (5)

Answer 25

• Bile acid sequestrants: Cholestyramine, Colestipol, and Colesevelam
• HMG-CoA reductase inhibitors (HMGRIs): Statins
• Cholesterol Absorption Inhibitor: Ezetimibe
• Fibrates: Gemfibrozil, Fenofibrate, etc.
• Inclisiran (small interfering RNA)

Question 26

Hyperlipidemia:
HMG-CoA reductase inhibitors
aka?

Answer 26

Statins
* Component of all cell membranes
* Precursor for androgens,
oestrogens, progesterone,
adrenocorticoids
* Natural products and synthetic agents
* Similar effects on plasma cholesterol
levels but differ in their indications, potencies, and PK profiles

Lower plasma cholesterol levels →inhibition of cholesterol
biosynthesis → inhibition of HMG-CoA reductase

Statins block access of HMG-CoA to the active site

Fungal metabolites, affinity for
HMG-CoA reductase in vivo
10,000-fold greater than HMG-CoA

Question 27

Hyperlipidemia
SAR of HMG-CoA reductase inhibitors

Answer 27

2 families (all designed with the open ring)

ALL have:
a) 3,5-dihydroxycarboxylate= essential
for inhibitory activity. pK a =2.5-3.5
ionised at physiologic pH
b) Absolute stereochemistry of OH in
3 (R) and 5 (R) must be same as
mevastatin and lovastatin
c) C=C can either increase or decrease
activity and 2 carbons are essential
between C5 and rig system

1. Mevastatin, Lovastatin, Simvastatin, etc.
   d) A bicyclic ring is essential for anchoring the compound to the enzyme active site
   e) R 2 = CH 3 more potent compound
   f) R 1 = OH more hydrophilic compound
2. Atorvastatin, Pitavastatin, Fluvastatin, etc.
   g) W, X, Y, and Z can be either C or N; n is
   equal to either zero or one (i.e., five- or
   six-member heterocyclic)
   h) R= aryl groups, hydrocarbon chains, amides,
   or sulfonamides enhances lipophilicity and
   inhibitory activity

Compound ending in -STATIN

Question 28

hyperlipidemia:
Cholesterol absorption inhibitor: Ezetimibe

Answer 28

• Bind to a specific cholesterol transport protein located in the wall of the small intestine
• Phenol OH (pk a = 9.7) help localise in the intestine and form the active glucuronide form (glucuronic acid attached to the OH)
• p-fluoro groups to block undesirable metabolism

Question 29

Hyperlipidemia:
What is the role of Fibrates?

Answer 29

• Decrease plasma triglyceride/cholesterol levels
• Exact mechanisms: not been fully elucidated
• Analogues of phenoxy isobutyric acid
• Isobutyric acid group is essential
• Fenofibrate: ester group , prodrug and
  requires in vivo hydrolysis