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3.23 > Lecture 6: Drug development in Cardiovascular disease > Flashcards

Lecture 6: Drug development in Cardiovascular disease Flashcards

1
Q

What are the properties that make a drug ‘drug like’

A
  • Selective for the target to avoid adverse effects
  • High affinity for the target
  • Chronic disease requires oral administration: Water solubility to allow for oral formulation (chronic disease treatment), Lipophilicity to allow absorption from the gastro-intestinal tract, Stability within the gastro-intestinal environment
  • Slow (hepatic) metabolism to allow for sustained activity and reduced dosing frequency
  • No toxic metabolites
  • Bodily distrinution to fascilitate access to the target and reduce eliminiation rate
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2
Q

How does the angiotensin cascade reduce blood pressure?

A

Reducing the amount of angiotensin II in the circulation - inhibiting angiotensin converting enzyme could achieve this

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3
Q

What makes ACE a good drug targer?

A
  • Its an enzyme that selectively binds a substrate (angiotensin I) and enzymes can be inhibited
  • Has a 3D active site that recognises a specific substrate, so building molecules to fit the site is possible
  • The enzyme is accessible - bound to membranes of endothelial cells and is particularly abundant in the lung, which has a bast surface area of vascular endothelium
  • Its also present in other vascular tissues (heart, striated muscle, kidney) all of which are well perfused
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4
Q

How does ACE convert angiotensin I to angiotensin II?

A

ACE hydrolyses peptide (amide) bond specifically between Phe and His on angiotensin I.

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5
Q

What is the end of a peptide chain called?

A

C terminus

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6
Q

What is the start of a peptide chain called?

A

N terminus

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7
Q

What does ACE have that helps amino acid side chains of angiotensin I fit into it?

A

Subside pockets

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8
Q

What prime pocket does Phe go into in ACE?

A

S1

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9
Q

What prime pocket does Leucine go into in ACE?

A

S2

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10
Q

What prime pocket does His go into in ACE?

A

S1’

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11
Q

What is the function of zinc in ACE?

A

Zinc ion in ACE active site, co-ordinates carbonyl of peptide bond to be hydrolysed. It polarises it and makes it more susceptible to hydrolysis

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12
Q

What groups does S1 bind to?

A

Aromatic groups

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13
Q

What groups does S2’ bind to?

A

Aliphatic groups

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14
Q

What groups does S2’ bind to?

A

Carboxylate group through an arginine sidechain in the pocket

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15
Q

What groups does S1’ bind to?

A

Aromatic/ aliphatic groups

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16
Q

What does the zinc ion bind to?

A

Electron rich/ negatively charged groups

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17
Q

What is a zinc metalloprotease?

A

Uses zinc in the active site to catalyse the hydrolysis of peptide substrates

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18
Q

What do all peptidases have?

A

S3/S2/S1/S1’ pockets

19
Q

What groups does the active site of ACE have?

A
  • Phenol
  • Leucine
  • His
20
Q

What groups does the active site of MMP1 have?

A
  • Asp
  • Ser
  • Pro
21
Q

What is teprotide?

A

A nonopeptide isolated from snake venom, was known to be an inhibitor of ACE

22
Q

What are the disadvantages of peptides as drugs? (3)

A
  • Peptides make poor drugs for oral administration
  • Sesceptible to degradation by peptidases in the GIT
  • Tend to be hydrophillic which reduces permeability through cell membranes
23
Q

What is succinyl-L-proline?

A

Succinic acid combined with proline

24
Q

What is the potency of succinyl-L-proline?

A

IC50 = 630

25
Q

How does succinyl-L-proline fit into ACE?

A
  • S1: no aromatic occupation
  • S2’: aliphatic group occupation
  • S2’ : can bind carboxylate group through an argenine sidechain in the pocket
  • S1” : no aromatic/ aliphatic groups to bind
  • Zinc ion can bind electron rich/ negatively charged group
26
Q

What group has the strongest interaction with the zinc ion?

A

Thiol group

27
Q

What is the dose of captopril?

A

25-50mg twice/ three times daily

28
Q

What is the logP of captopril?

A

0.62

29
Q

What is the solubility of captopril?

A

4.52mg/ml

30
Q

What is the bioavailability of captopril?

A

60-70%

31
Q

What is the half life of captopril?

A

2 hours

32
Q

What is the primary route of administartion of captopril?

A

Renal excretion

33
Q

What are the common side effects of captopril?

A
  • Rashes
  • Loss of taste
34
Q

How are the side effects of captopril removed?

A

If the thiol group is replaced with carboxylate

34
Q

How are the side effects of captopril removed?

A

If the thiol group is replaced with carboxylate

35
Q

What is the dose of enalapril?

A

2.5mg once daily

36
Q

What is the logP of enalapril?

A

0.7

37
Q

What is the bioavailability of enalapril?

A

60%

38
Q

What is the half life of enalapril?

A

12 hours

39
Q

What is the primary route of elimination of enalapril?

A

Renal excretion

40
Q

What is the plasma protein binding of enalapril?

A

50-60%

41
Q

How is prodrug ramipril activated?

A

Hydrolysis

42
Q

What is the active form of ramipril?

A

Ramiprilat

3.23 (26 decks)

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