Chemistry of CV drugs Flashcards
1
Q
What is the broad definition of cardiovascular disease (CVD)?
A
Conditions affecting the heart or blood vessels
2
Q
What is a key risk factor for cardiovascular disease, like stroke and heart attack?
A
Hypertension
3
Q
Why is reducing blood pressure effective for lowering CVD risk?
A
It lowers the risk of stroke and heart attack
4
Q
What does RAAS stand for?
A
Renin-Angiotensin-Aldosterone System
5
Q
What three things is the RAAS central to maintaining?
What happens when the RAAS cascade becomes too active?
A
Blood volume, arterial BP, electrolyte balance
Abnormally high levels of angiotensin II
6
Q
Angiotensin II promotes the release of which hormone?
A
Aldosterone
7
Q
What is cleaved to form angiotensin I?
A
Angiotensinogen
8
Q
Where is renin produced?
A
Kidneys
9
Q
Why will blocking the synthesis of angiotensin I lower angiotensin II levels?
A
Angiotensin I is the substrate for ACE
10
Q
What enzyme converts angiotensin I to angiotensin II?
A
ACE (Angiotensin Converting Enzyme)
11
Q
What animal’s venom contains teprotide?
A
South American pit viper
12
Q
Why does teprotide have limited therapeutic activity?
A
It is a peptide with poor oral activity
13
Q
Drugs were designed based on the structure of what ACE inhibitor?
A
Teprotide
14
Q
What is the ionisation state of the carboxylate groups of succinyl-L-proline at physiological pH?
A
Both carboxylate groups will be ionised
15
Q
What two molecules are reacted in the synthesis of enalaprilat?
A
Ketoacid and the dipeptide L-ala-L-pro
16
Q
What type of reaction is involved in converting a carbonyl group to an amine via an imine?
A
Reductive amination
17
Q
What functional group does captopril contain?
A
Sulfhydryl (SH)
18
Q
Why did sulfhydryl compounds get replaced in ACE inhibitors?
A
High incidences of skin rash and taste disturbance
19
Q
Which angiotensin II receptor is primarily responsible for vasoconstriction?
A
AT1 receptor
20
Q
What year were Angiotensin receptor antagonists (ARA’s), known as sartans produced?
A
1990s
21
Q
What year was losartan approved?
A
1995
22
Q
How is losartan converted to a more potent antagonist?
A
Oxidatively metabolised
23
Q
What is the role of the carboxylic acid group in losartan?
A
Message for receptor antagonism
24
Q
What is the role of the hydrophobic group and acidic tetrazole group in losartan?
A
Address that directs to AT1 receptor
25
What type of receptor is the B1‒adrenoreceptor?
G-Protein-coupled receptor
26
What does activation of B1‒adrenoreceptors result in?
Cardiac muscle contraction
27
What happens when B‒blockers bind to B‒adrenoreceptors?
Block the binding of noradrenaline/adrenaline
28
What structural similarity do B‒blockers have?
Similarity to noradrenaline and adrenaline
29
What can changing the structure of isoprenaline do?
Convert it to an antagonist
30
What condition is Propranolol used to treat?
Angina
31
What year did James Black receive the Nobel Prize for Medicine?
1988
32
What enantiomer of Propranolol is the active form?
S-enantiomer
33
What is the role of the ether oxygen in aryloxypropanolamines?
Act as an HBA
34
What is the role of the alcohol group in the side chain of aryloxypropanolamines?
Essential in H-bonding
35
What type of bonding is involved between N+ and the receptor?
Ionic bonding
36
What is the difference between first and second-generation B-blockers?
Second-generation are B1-selective
37
What was the first cardioselective B1-blocker?
Practolol
38
Why was practolol withdrawn from the market? What position must the amido group be in for B1-selectivity?
Unexpected S/Es
Para position
39
What is a commonly prescribed B‒blocker used to treat hypertension?
Atenolol
40
What do antihypertensives usually block the actions of?
Endogenous hormones with vasoconstricting properties
41
How do vasodilators work?
Actively promote the dilation of blood vessels
42
What can vasodilators be used in treatment of?
Angina or hypertension
43
What gaseous signaling molecule activates guanylate cyclase? What secondary messenger is produced by guanylate cyclase?
NO (nitric oxide)
Cyclic GMP
44
How does NO activate guanylate cyclase?
Binds to ferrous ion in a haem complex
45
How do glyceryl trinitrate, isosorbide mononitrate, and isosorbide dinitrate work?
Provide a source of nitrate ions (NO3-)
46
How does Riociguat work?
Stabilises the nitrosyl-haem complex
47
What is sodium nitroprusside used for?
Treating hypertension emergencies
48
What was Sildenafil (Viagra) originally designed as?
Vasodilator to treat angina/hypertension
49
What is the effect of inhibiting phosphodiesterase-5?
Prolongs activity as a vasodilator
50
What do Neprilysin Inhibitors do?
Inhibit hydrolysis of hormones that act as vasodilators
51
What do Prostacyclin Agonists do?
Potent vasodilator
52
What are some side effects produced by Type I statins?
Muscle pain and liver damage
53
For benzothiazepines, what is the effect of a methoxy substituent on the phenyl group for activity?
Increases activity 15-fold
54
What is the Hantzsch dihydropyridine synthesis in the context of nifedipine synthesis?
- Synthesis of dihydropyridines from aldehydes, β-ketoesters, and ammonia
- Formation of the 1,4-dihydropyridine ring.
- Involves a multi-component reaction
55
What is the Claisen-Schmidt condensation mechanism in the context of nifedipine synthesis?
- A crossed aldol condensation reaction
- Forms a carbon-carbon bond between two carbonyl compounds.
- One carbonyl compound acts as nucleophile
- Other carbonyl compound undergoes deprotonation and nucleophilic attack
56
How does the pyridine ring's planarity affect the orientation of substituents on the aromatic ring in nifedipine?
Substituents point away from the DHP ring
57
What type of hydrogen bonding interactions occur between nifedipine and its target?
Hydrogen bond donors and acceptors
58
Although size and position are emphasized in dihydropyridines SAR, what other factor plays a less significant role?
Electronic factors
59
What is the impact of the allosteric linkage between calcium entry blocker binding sites on drug interactions?
Influences the binding of neighbouring drugs
60
Besides dihydropyridines and benzothiazepines, what is another structural class of calcium entry blockers (CEBs)?
Phenylalkylamines
61
What condition can occur if thrombi are dislodged?
Thromboembolism
62
What is an advantage of factor Xa inhibitors?
Fewer S/Es
63
What do factor Xa inhibitors catalyse?
Covnersion of prothrombin to thrombin
64
What type of reaction converts the prodrug dabigatran etexilate into the active drug dabigatran?
Hydrolysis
65
What monoclonal antibody can reverse the anticoagulant properties of dabigatran? What is dabigatran administered as?
Idarucizumab
The prodrug dabigatran etexilate
66
What ring system is an important base for thrombin inhibitors?
Trisubstituted benzimidazole ring
67
How do heparins, like enoxaparin, inhibit thrombin's activity?
Bind to thrombin
68
What are some drawbacks of Warfarin use?
Low therapeutic index and drug-drug interactions
69
Which type of calcium ion channels are most important in cardiovascular medicine?
Voltage gated L-type calcium ion channels
70
What do voltage-gated L-type calcium ion channels respond to? Which subunit of the L-type calcium ion channel controls the flow of calcium ions?
Changes in membrane potential
The α1 subunit
71
What is the main use of drugs that prevent calcium ions from crossing the ion channel?
Hypertension, angina, and other CV diseases
72
What are the three main structural classes of calcium entry blockers (CEBs)?
- Dihydropyridines
- Benzothiazepines
- Phenylalkylamines
73
Where do each of the calcium entry blocker classes bind on the α1 subunit?
Distinct bonding regions
74
What kind of linkage exists between the binding sites of calcium entry blockers on the α1 subunit?
Allosterically linked
75
What effect does a drug binding to one binding site have on another drug binding to a neighboring site?
It influences its ability
76
What are dihydropyridine calcium channel blockers derivatives of?
1,4-dihydropyridine
77
What are dihydropyridine calcium channel blockers primarily used to treat?
Hypertension
78
For dihydropyridines, what substitution on the phenyl ring is considered beneficial for activity? What is essential at the C3 and C5 positions of dihydropyridines to optimise activity?
Ortho and meta substitution
Ester groups
79
What type of groups at C3 and C5 can produce agonist activity in dihydropyridines?
Other EWG
80
For phenyl ring substitution in dihydropyridines, what is important besides electronic factors?
Size and position
81
What effect does a substituent in the para position have on the activity of dihydropyridines?
Bad for activity
82
What part of the 1,4-DHP ring is essential for activity and should remain unsubstituted?
N1
83
What ring system is essential for the activity of nifedipine?
The 1,4-DHP ring
84
What happens to activity when piperidine or pyridine systems are used instead of the 1,4-DHP ring?
Greatly decreases or abolishes activity
85
What role does the ortho NO2 group play in nifedipine's structure?
Provides steric bulk and ensures perpendicularity
86
What effect does the pyridine ring's planarity have on the orientation of the aromatic ring and its substituents?
Significant effect
87
In the active conformation of dihydropyridines, where do substituents on the aromatic ring point?
Away from the dihydropyridine ring
88
What are the two steps in the synthesis of nifedipine?
Claisen-Schmidt Condensation and Hantzsch Dihydropyridine Synthesis
89
What type of reaction is the Claisen-Schmidt Condensation?
Crossed aldol condensation reaction
90
What does amlodipine's increased potency compared to nifedipine suggest about the 1,4-DHP receptor?
It can tolerate larger substituents
91
What property does the C4 carbon gain in amlodipine due to the different esters at C3 and C5?
Chirality
92
How many benzene rings are attached to the thiazepine ring in benzothiazepines? How many benzene rings are attached to the thiazepine ring in dibenzothiazepines?
1
2
93
What are dibenzothiazepines frequently used to treat?
Neuropsychiatric disorders
94
What kind of disorders are schizophrenia and bipolar disorder?
Neuropsychiatric disorders
95
For benzothiazepines, what is the effect of a -OCH3 group, and of larger alkyl groups?
-OCH3 beneficial, larger alkyl groups detrimental
96
What groups are considered beneficial on the benzene ring of benzothiazepines?
CH3 and Cl
97
How crucial is the activity of benzene rings on benzothiazepines? For benzothiazepines, how important is activity to the benzene ring?
Not crucial
Important
98
Excess levels of what substances can be a major risk factor for CVD?
Cholesterol and other lipids
99
What are the drugs used to lower cholesterol?
- Statins
- Fibrates
100
What do statins competitively inhibit in cholesterol biosynthesis?
HMG-CoA reductase (enzyme)
101
What is converted to mevalonate in cholesterol biosynthesis?
HMG-CoA
102
In the conversion of HMG-CoA to mevalonate, what is the role of NADPH?
Source of hydride (H-) ions
103
What common structural feature do all statins share?
A polar 'head group' linked to a hydrophobic group
104
Why does simvastatin, containing a lactone ring, still function effectively to lower cholesterol?
The lactone is converted to an active acyclic form
105
What is a disadvantage of Type I statins besides side effects?
Difficult to synthesize due to chiral centers
106
Why do statins bind more strongly than the natural substrate HMG-SCoA?
Statins are transition-state analogues
107
What does it mean for statins to act as transition-state analogues?
They resemble the transition state
108
What is the result of drugs that resemble the transition state for a catalyzed reaction?
They bind more strongly
109
What do antithrombotic agents counter?
The effect of thrombosis
110
When is a thrombus considered harmful? What can thrombosis result in?
When it obstructs blood flow in healthy vessels
Acute MI and stroke
111
What are the three classifications of antithrombotic agents?
- Anticoagulants
- Antiplatelet Agents
- Fibrinolytic Agents
112
What is the primary function of anticoagulants?
Prevent thrombus development in the venous system
113
What is the function of Warfarin?
Prevents the recycling of vitamin K
114
What is vitamin K's role?
Important co-factor required by enzymes
115
Which enzyme does Warfarin inhibit?
Vitamin K 2,3 epoxide reductase
116
Why does the release of aldosterone cause an increase in BP?
Aldosterone promotes increased fluid retention in the kidneys
Increasing blood volume
Increasing BP
117
What are the modifiable risk factors for CVD?
High BP
Smoking
Diabetes mellitus
Physical activity
Obesity
High blood cholesterol
118
What are the non-modifiable risk factors of CVD?
Age
Gender
Genetics
Race & ethnicity
119
What binding interactions will take place between succinyl proline and the ACE?
Negatively charged groups can bind to positively charged amino acid residues and metal ions
Amide oxygen can also act as a H-bond acceptor
120
With the binding interactions between succinyl proline and the enzyme, how can additional binding interactions be introduced?
Extra binding interaction introduced to bond with the S1 and S1' pockets
Using enalaprilat bound to the enzyme active site
Stereochemistry of the chiral carbons are a key factor
121
Why do you think there is an ester functional group when an ionic interaction is necessary for ramiprilat activity?
Ramiprilat has very poor oral bioavailability
Esterification of ramiprilat produces a compound with superior bioavailability
122
What group in losartan is easily oxidised?
Primary alcohol oxidised to aldehyde
Further oxidised to carboxylic acid
123
Looking at pronethalol's structure, explain why this is now not a full b-agonist
Extra aromatic ring causes an extra hydrophobic binding interaction with the receptor which is not involved when the agonist binds
Means a different induced fit
So ligand binds without activating the receptor
124
Why could propranolol not be used to treat asthmatic patients?
Antagonism of b2-adrenoceptors constricts airways
125
What hydrogen bonding interactions occur between nifedipine and its target?
Me(O2)C - HBA
N - (H) - HBD
C(O2)Me - HBA
(NO2) - HBA
126
Why is the basic tertiary amine crucial for benzothiazepine activity? Why are ortho and meta substituents on the phenyl group are not well tolerated? Why does a metoxy substituent of the phenyl group increase activity by 15-fold? Why is activity lost if larger alkoxy groups are present?
1. Protonated amine allows both ionic and hydrogen bonding interactions
2. Aromatic ring confined in hydrophobic pocket
3. Oxygen acts as hydrogen bond acceptor
4. Same as (2) that aromatic ring is confined to hydrophobic pocket
127
What is the role of the NADP in the conversion of HMG-CoA to mevalonate?
It acts as a co-factor for the enzyme catalysed reaction by acting as a reducing agent
128
Why do statins bind more strongly than the natural substrate? Why are they resistant to the enzyme catalysed reaction?
Extra hydrophobic region forms additional hydrophobic interactions with hydrophobic binding regions in enzyme
Allows statins to bind more strongly
- Statins are resistant to enzyme-catalysed reaction since coenzyme-A in substrate (acts as leaving group) has been replaced by hydrophobic group
- That cannot act as a leaving group
129
What type of reaction converts the prodrug into the active drug as dabigatran?
Ester hydrolysis
Amide hydrolysis
