L 18 Medicinal Chemistry of Hypertension Flashcards
What Hypertension causes?
decreased vascular tone.
Hypertension can be risk factors for many other disease?
Stroke, Myocardial infarction (IHD)
Heart Failure(HF)
Atrial fibrillation (AF)
Chronic Kidney Disease(CKD)
What target drug in RAA (Renin angiotensin aldosterone) system?
Angiotensinogen is a 452 protein, which hydrolyzed by renin and produces angiotensin I,
then it further converted by angiotensin-converting enzyme and form angiotensin ii than it makes the signals to GPCR.
(Remember if Angiotensin ii is high in our blood cause hypertension, so drug target is Angiotensin ii)
Why we can’t just use peptides?
Because they hydrolyzed easily. Not good.
What are the types of angiotensin II receptor subtypes?
AT1 receptor and AT2 receptor
Angiotensin II is an … at both … and …
Angiotensin II is an endogenous agonist at both AT1R and AT2R
Drugs that are angiotensin II ‘blockers’ are thought to be … …
AT1R antagonists
What are the 3 different drug targets for hypertension?
- Renin
- ACE (angiotensin-converting enzyme)
- AT2R (Angiotensin 2 Receptor)
What are the Adv and Dis of peptide drugs:
Adv: highly specific and high affinity for target
Disadv: hydrolysed quickly = poor stability & low oral bioavailability.
ACE inhibitors + examples (x6)
e.g captopril, enalapril, cilazapril, perindopril, quinapril, lisinopril.
Is lisinopril a prodrug?
Not
Which ACEI are administered in their active form?
Lisinopril and captopril
Is losartan a prodrug? What class of drug is losartan?
No, because technically both losartan and its metabolite have biological activity.
Drug class = Angiotensin II Receptor Blocker (ARB)
Is the candesartan cilexetil a prodrug?
Yes
Ester hydrolysis of Candesartan occurs during…?
Absorption from the GIT
What are the Examples of Angiotensin II Receptor Blockers?
Losartan, candesartan, irbesartan
Which part of the losartan bind to the target and with which help?
Carboxylic acid moiety binds with the target. With the hlep of CYP 2C9 & 3A4 enzyme.
Is losartan a prodrug?
No
Which receptors do angiotensin II blockers act at?
AT1 receptors
Calcium Channel Blockers act at… by binding to the …
CCBs act at L-type voltage-gated calcium channels by binding to the alpha i subunit of the membrane spanning protein.
Examples of DHP calcium channel blockers in NZ. Which of these are racemic mixtures?
Amlodipine, felodipine, isradipine, nifedipine, nimodipine. (the core is 1,4, DHP)
All are racemic except nifedipine.
The structure of Dihydropyridines (DHP) of Calcium channel blockers has?
Esters at C3 and C5 and Phenyl ring at C4 of 1,4 Di Hydro Pyridine.
Non DHP Calcium Channel Blockers examples:
Verapamil, diltiazem
Stimulation of B1 in the heart causes.?
Increased heart rate, contractility, AV node conduction and cardiac output.
What will B2AR agonists cause… therefore B2AR antagonists will cause….?
B2AReceptor agonists cause bronchodilation therefore B2AR antagonists will cause bronchoconstriction
What if A1AR antagonists will cause…
Vasodilation of blood vessels (therefore decrease in resistance and blood pressure).
Examples of B1AR blockers
Prazosin, terazosin, doxazosin
Does AR bind with both B1 and B2?
Yes but they do not elicit a receptor signal or do not work as antagonists.
Remember that the First generation is non selective but 2nd generation is selective
Does AR bind with both B1 and B2?
Yes but they do not elicit a receptor signal or do not work as antagonists.
Remember that the First generation is nonselective but 2nd generation is selective
BAR and XAR are … to each other
Beta and alpha adrenoreceptors are structurally different to each other.
Which one is more lipophilic and can more cross BBB?
Propranolol or Nadolol or Pindolol
Propranolol as its clogp is higher than other its 2.58 and can cross BBB.
First generation BAR blockers are selective for … but are not selective for ….
First generation BAR blockers are selective for bAR over xAR but are not selective for b1AR over b2AR
B blockers are a ……
B blockers are a racemic mixture.
Examples of Non-selective B blockers
Propanolol, nadolol, pindolol
Which of the following are the most lipophilic?
ClogP: 2.58 ClogP: 0.87 ClogP: 1.69 Highest clogP = more lipophilic Therefore 2.58 is the most lipophilic
A more lipophilic drug is …. likely to diffuse across the BBB
More lipophilic = more likely to diffuse across membrane
Lipophilic B blockers can cause…
Nightmares, sleep disturbances, hallucinations
Second generation B blockers are selective for …
Selective for BAR over alpha AR and selective for B1AR over B2AR
Why is B1 selectivity desirable?
B1 selectivity can target the heart without getting unwanted side effects in the lungs, therefore can be used in asthmatics.
How do you make a B1 selective blocker? What functional group do you add?
Changing the drug structure to favour B1 means that it no longer will bind well in the other subtypes.
Add a functional group off the phenyl ring that is capable of hydrogen bonding.
How do we design a drug with a short duration of action?
Make it as ester to be rapidly cleaved in the body.Ex esmolol
Examples of selective 2nd generation B blockers
Metoprolol, atenolol
Examples of drugs that bind to both x1, B1 and B2 ARs. What structural difference do they have?
Labetalol, carvedilol
Have an extended chain with an aromatic group.
What do diuretics do?
They increase the rate of urine formation
Examples of different diuretic classes + examples within these classes
Thiazides (e.g bendroflumethiazide) Loop diuretics (e.g furosemide)
How do thiazide diuretics work?
Blocks Na+Cl- symporter, causing less Na+ reabsorption (and therefore less water reabsorption).
Lower Na+ also causes vasodilation
Structural requirements of thiazides
Electron withdrawing group, sulfonamide, lipophilic group
How do loop diuretics work?
Inhibiting Na/K/2Cl co-transporter (aka NKCC2) therefore more excretion of Na+ and water.
They treat edema and can help hypertension
