Chemistry of CV drugs Flashcards
What is the broad definition of cardiovascular disease (CVD)?
Conditions affecting the heart or blood vessels
What is a key risk factor for cardiovascular disease, like stroke and heart attack?
Hypertension
Why is reducing blood pressure effective for lowering CVD risk?
It lowers the risk of stroke and heart attack
What does RAAS stand for?
Renin-Angiotensin-Aldosterone System
What three things is the RAAS central to maintaining?
What happens when the RAAS cascade becomes too active?
Blood volume, arterial BP, electrolyte balance
Abnormally high levels of angiotensin II
Angiotensin II promotes the release of which hormone?
Aldosterone
What is cleaved to form angiotensin I?
Angiotensinogen
Where is renin produced?
Kidneys
Why will blocking the synthesis of angiotensin I lower angiotensin II levels?
Angiotensin I is the substrate for ACE
What enzyme converts angiotensin I to angiotensin II?
ACE (Angiotensin Converting Enzyme)
What animal’s venom contains teprotide?
South American pit viper
Why does teprotide have limited therapeutic activity?
It is a peptide with poor oral activity
Drugs were designed based on the structure of what ACE inhibitor?
Teprotide
What is the ionisation state of the carboxylate groups of succinyl-L-proline at physiological pH?
Both carboxylate groups will be ionised
What two molecules are reacted in the synthesis of enalaprilat?
Ketoacid and the dipeptide L-ala-L-pro
What type of reaction is involved in converting a carbonyl group to an amine via an imine?
Reductive amination
What functional group does captopril contain?
Sulfhydryl (SH)
Why did sulfhydryl compounds get replaced in ACE inhibitors?
High incidences of skin rash and taste disturbance
Which angiotensin II receptor is primarily responsible for vasoconstriction?
AT1 receptor
What year were Angiotensin receptor antagonists (ARA’s), known as sartans produced?
1990s
What year was losartan approved?
1995
How is losartan converted to a more potent antagonist?
Oxidatively metabolised
What is the role of the carboxylic acid group in losartan?
Message for receptor antagonism
What is the role of the hydrophobic group and acidic tetrazole group in losartan?
Address that directs to AT1 receptor
What type of receptor is the B1‒adrenoreceptor?
G-Protein-coupled receptor
What does activation of B1‒adrenoreceptors result in?
Cardiac muscle contraction
What happens when B‒blockers bind to B‒adrenoreceptors?
Block the binding of noradrenaline/adrenaline
What structural similarity do B‒blockers have?
Similarity to noradrenaline and adrenaline
What can changing the structure of isoprenaline do?
Convert it to an antagonist
What condition is Propranolol used to treat?
Angina
What year did James Black receive the Nobel Prize for Medicine?
1988
What enantiomer of Propranolol is the active form?
S-enantiomer
What is the role of the ether oxygen in aryloxypropanolamines?
Act as an HBA
What is the role of the alcohol group in the side chain of aryloxypropanolamines?
Essential in H-bonding
What type of bonding is involved between N+ and the receptor?
Ionic bonding
What is the difference between first and second-generation B-blockers?
Second-generation are B1-selective
What was the first cardioselective B1-blocker?
Practolol
Why was practolol withdrawn from the market? What position must the amido group be in for B1-selectivity?
Unexpected S/Es
Para position
What is a commonly prescribed B‒blocker used to treat hypertension?
Atenolol
What do antihypertensives usually block the actions of?
Endogenous hormones with vasoconstricting properties
How do vasodilators work?
Actively promote the dilation of blood vessels
What can vasodilators be used in treatment of?
Angina or hypertension
What gaseous signaling molecule activates guanylate cyclase? What secondary messenger is produced by guanylate cyclase?
NO (nitric oxide)
Cyclic GMP
How does NO activate guanylate cyclase?
Binds to ferrous ion in a haem complex
How do glyceryl trinitrate, isosorbide mononitrate, and isosorbide dinitrate work?
Provide a source of nitrate ions (NO3-)
How does Riociguat work?
Stabilises the nitrosyl-haem complex
What is sodium nitroprusside used for?
Treating hypertension emergencies
What was Sildenafil (Viagra) originally designed as?
Vasodilator to treat angina/hypertension
What is the effect of inhibiting phosphodiesterase-5?
Prolongs activity as a vasodilator
What do Neprilysin Inhibitors do?
Inhibit hydrolysis of hormones that act as vasodilators
What do Prostacyclin Agonists do?
Potent vasodilator
What are some side effects produced by Type I statins?
Muscle pain and liver damage
For benzothiazepines, what is the effect of a methoxy substituent on the phenyl group for activity?
Increases activity 15-fold
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
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
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
What type of hydrogen bonding interactions occur between nifedipine and its target?
Hydrogen bond donors and acceptors
Although size and position are emphasized in dihydropyridines SAR, what other factor plays a less significant role?
Electronic factors
What is the impact of the allosteric linkage between calcium entry blocker binding sites on drug interactions?
Influences the binding of neighbouring drugs
Besides dihydropyridines and benzothiazepines, what is another structural class of calcium entry blockers (CEBs)?
Phenylalkylamines
What condition can occur if thrombi are dislodged?
Thromboembolism
What is an advantage of factor Xa inhibitors?
Fewer S/Es
What do factor Xa inhibitors catalyse?
Covnersion of prothrombin to thrombin
What type of reaction converts the prodrug dabigatran etexilate into the active drug dabigatran?
Hydrolysis
What monoclonal antibody can reverse the anticoagulant properties of dabigatran? What is dabigatran administered as?
Idarucizumab
The prodrug dabigatran etexilate
What ring system is an important base for thrombin inhibitors?
Trisubstituted benzimidazole ring
How do heparins, like enoxaparin, inhibit thrombin’s activity?
Bind to thrombin
What are some drawbacks of Warfarin use?
Low therapeutic index and drug-drug interactions
Which type of calcium ion channels are most important in cardiovascular medicine?
Voltage gated L-type calcium ion channels
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
What is the main use of drugs that prevent calcium ions from crossing the ion channel?
Hypertension, angina, and other CV diseases
What are the three main structural classes of calcium entry blockers (CEBs)?
- Dihydropyridines
- Benzothiazepines
- Phenylalkylamines
Where do each of the calcium entry blocker classes bind on the α1 subunit?
Distinct bonding regions
What kind of linkage exists between the binding sites of calcium entry blockers on the α1 subunit?
Allosterically linked
What effect does a drug binding to one binding site have on another drug binding to a neighboring site?
It influences its ability
What are dihydropyridine calcium channel blockers derivatives of?
1,4-dihydropyridine
What are dihydropyridine calcium channel blockers primarily used to treat?
Hypertension
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
What type of groups at C3 and C5 can produce agonist activity in dihydropyridines?
Other EWG
For phenyl ring substitution in dihydropyridines, what is important besides electronic factors?
Size and position
What effect does a substituent in the para position have on the activity of dihydropyridines?
Bad for activity
What part of the 1,4-DHP ring is essential for activity and should remain unsubstituted?
N1
What ring system is essential for the activity of nifedipine?
The 1,4-DHP ring
What happens to activity when piperidine or pyridine systems are used instead of the 1,4-DHP ring?
Greatly decreases or abolishes activity
What role does the ortho NO2 group play in nifedipine’s structure?
Provides steric bulk and ensures perpendicularity
What effect does the pyridine ring’s planarity have on the orientation of the aromatic ring and its substituents?
Significant effect
In the active conformation of dihydropyridines, where do substituents on the aromatic ring point?
Away from the dihydropyridine ring
What are the two steps in the synthesis of nifedipine?
Claisen-Schmidt Condensation and Hantzsch Dihydropyridine Synthesis
What type of reaction is the Claisen-Schmidt Condensation?
Crossed aldol condensation reaction
What does amlodipine’s increased potency compared to nifedipine suggest about the 1,4-DHP receptor?
It can tolerate larger substituents
What property does the C4 carbon gain in amlodipine due to the different esters at C3 and C5?
Chirality
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
What are dibenzothiazepines frequently used to treat?
Neuropsychiatric disorders
What kind of disorders are schizophrenia and bipolar disorder?
Neuropsychiatric disorders
For benzothiazepines, what is the effect of a -OCH3 group, and of larger alkyl groups?
-OCH3 beneficial, larger alkyl groups detrimental
What groups are considered beneficial on the benzene ring of benzothiazepines?
CH3 and Cl
How crucial is the activity of benzene rings on benzothiazepines? For benzothiazepines, how important is activity to the benzene ring?
Not crucial
Important
Excess levels of what substances can be a major risk factor for CVD?
Cholesterol and other lipids
What are the drugs used to lower cholesterol?
- Statins
- Fibrates
What do statins competitively inhibit in cholesterol biosynthesis?
HMG-CoA reductase (enzyme)
What is converted to mevalonate in cholesterol biosynthesis?
HMG-CoA
In the conversion of HMG-CoA to mevalonate, what is the role of NADPH?
Source of hydride (H-) ions
What common structural feature do all statins share?
A polar ‘head group’ linked to a hydrophobic group
Why does simvastatin, containing a lactone ring, still function effectively to lower cholesterol?
The lactone is converted to an active acyclic form
What is a disadvantage of Type I statins besides side effects?
Difficult to synthesize due to chiral centers
Why do statins bind more strongly than the natural substrate HMG-SCoA?
Statins are transition-state analogues
What does it mean for statins to act as transition-state analogues?
They resemble the transition state
What is the result of drugs that resemble the transition state for a catalyzed reaction?
They bind more strongly
What do antithrombotic agents counter?
The effect of thrombosis
When is a thrombus considered harmful? What can thrombosis result in?
When it obstructs blood flow in healthy vessels
Acute MI and stroke
What are the three classifications of antithrombotic agents?
- Anticoagulants
- Antiplatelet Agents
- Fibrinolytic Agents
What is the primary function of anticoagulants?
Prevent thrombus development in the venous system
What is the function of Warfarin?
Prevents the recycling of vitamin K
What is vitamin K’s role?
Important co-factor required by enzymes
Which enzyme does Warfarin inhibit?
Vitamin K 2,3 epoxide reductase
Why does the release of aldosterone cause an increase in BP?
Aldosterone promotes increased fluid retention in the kidneys
Increasing blood volume
Increasing BP
What are the modifiable risk factors for CVD?
High BP
Smoking
Diabetes mellitus
Physical activity
Obesity
High blood cholesterol
What are the non-modifiable risk factors of CVD?
Age
Gender
Genetics
Race & ethnicity
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
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
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
What group in losartan is easily oxidised?
Primary alcohol oxidised to aldehyde
Further oxidised to carboxylic acid
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
Why could propranolol not be used to treat asthmatic patients?
Antagonism of b2-adrenoceptors constricts airways
What hydrogen bonding interactions occur between nifedipine and its target?
Me(O2)C - HBA
N - (H) - HBD
C(O2)Me - HBA
(NO2) - HBA
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?
- Protonated amine allows both ionic and hydrogen bonding interactions
- Aromatic ring confined in hydrophobic pocket
- Oxygen acts as hydrogen bond acceptor
- Same as (2) that aromatic ring is confined to hydrophobic pocket
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
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
What type of reaction converts the prodrug into the active drug as dabigatran?
Ester hydrolysis
Amide hydrolysis
