Lecture 6 - ACE inhibitors Flashcards
what properties o we need our drugs to have to be classed as ‘drug-like’?
selectivity for the target to avoid adverse effects
high affinity for the target (potency)
chronic disease requires oral administration
- water solubility
-lipophilicty to allow absorption from the gastrointestinal tract
- stability within the GI environment
slow, hepatic metabolism to allow for sustained activity and reduced design frequency
no toxic metabolites
bodily distribution to facilitate access to the target and reduce elimination rate
why was ACE considered a ‘good’ drug target?
it has an exam that selectively binds a substrate
9angiotensin I) and enzymes can be inhibited
it has a 3 dimensional active site that recognises a specific substrate, so building molecules for fit the site is possible
inhibition of CE with peptides resembling the substrate had been shown to reduce the conversion of angiotensin I to II experimentally
the enzyme is accessible - it is bound to the membranes of endothelial cells and is particularly abundant in the lung, which has a vast surface area of vascular endothelium
also present in other vascular tissues (heart, striated muscle, kidney) all of which are well perfused
what is the target of ACE in angiotensin I ?
ACE hydrolyses peptide bond specifically between The and His to form Angiotensin II and his-leu
how do the amino acid side chains of angiotensin I fit into active sites of ACE subsite pockets ?
by complementary interactions
what does the zinc ion in ACE acute site do?
zinc ion in ACE active site co-ordinates carbonyl of peptide bond to be hydrolysed - polarises it and makes it more susceptible to hydrolysis
what are the key features for substrate- ACE interactions?
S1 can bind aromatic groups
S2’ can bin aliphatic groups
can bind a carboxylate group through an arginine side chain in the pocket
S1’ can bind aromatic/ aliphatic groups
zinc ion can bind electron rich/ negatively charged groups
what are the selectivity requirements of ACE as a target?
ACE is a zinc metalloprotease (uses zinc in the active site to catalyse the hydrolyses of peptide substrates)
there are many zinc metalloproteases that perform essential function
an ACE inhibitor would have to be selective for ACE and avoid inhibition of other metalloproteases (and other proteases in general)
what does MMP1 zinc metalloprotease cleave?
MMP1 zinc metalloprotease cleaves its PAR-1 substrate between Asp and pro
what should new CE inhibitors must recognise?
new ACE inhibitors must recognise ACE subsites, but not MMP1 (and other proteases) otherwise side effects/ adverse effects will emerge
what are the key features for substrate- MMP1 interactions?
S1 can bind acidic groups
S2’ can bind aliphatic bonding groups and H bonding groups
S1’ can bind aliphatic groups
zinc ion can bind electron rich/ negatively charged groups
name a lead in ACE as a target and what peptide is common for ace inhibition?
Teproide a nonopeptide form snake venom was known to be an inhibitor of ACE
pro was found to be a common C-termianl amino cid in other peptides that inhibited ACE
what are disadvantages of peptides as drugs?
peptides make poor drugs for oral administration
- susceptible to degradation by peptidases in the GIT
- tend to be hydrophilic which reduces permeability through cell membranes
describe benzylsuccinic acid and how it is optimised as a target substrate for ACE
poor potency compared to teprotide
not selective for ACE: inhibited many peptidases
no peptide/amide bond it was not hydrolysed by ACE
- combined succinic acid with proline:
S2’ aliphatic groups occupation
S2’ can bind a carboxylate group through an arginine side chain in the pocket
zinc ion can bind electron rich/ entirely charged group
no S1’ substituent in sustarte - introduce an alkyl group —> S1’ can bind methyl group
what was changed in the sucking-prolien molecule to make and why?
thiol group replaced carboxylic acid - which binds to zn cause thiol group has a stronger interaction with the Zn ion
- this leads to r centre from succine-proline to captopril s centre
describe the structure -a activity relationship from benzylsuccinic acid to make captopril
R methyl improves potency compared to H
S from R methyl improves potency
from carboxylate to thiol group improves potency
adding a carboxylate improves potency
what are captopril PK and clinical considerations ?
dose: 25 - 50 mg twice/three times adil y
log P = 0.62
solubility 4.52 mg/ml
bioavailability: 60-70%
plasma protein binding = 30%
Vd = 0.7 L/kg
half life = 2 hrs
primary route of elimination = renal excretion
when introduced, normalised blood pressure of 50% of hypertensive population treated
when combined with a diuretic, 90% of the population improved
what are side effects of captopril and what it the effect of the drug I replaced thiol with a carboxylate?
common side effects - rashes and loss of taste
if thiol replaced with carboxylate,
- potency too low for an effective drug (dose needed is too high)
- lipophilicity too low for good absorption
how os the potency of carboxyalkanoylproline improved?
add aromatic ring to make enalaprilat for additional aromatic pocket for the S1 subsite in the ACE active site
why does enalaprilat have poor physical properties?
due to the carboxylate group, lipophilcity it too low for good absorption
why does enalaprilat have poor physical properties?
due to the carboxylate group, lipophilcity it too low for good absorption
what is enalapril and the purpose?
carboxylate group is converted to a more lipophilic ethyl ester.
the hydrophilic carboxyl group can be masked temporarily by preparing the more lipophilic ethyl ester - enalapril
what does liver esterase do?
hydrolyse enalapril to enalaprilat on first pass through the liver as soon as it is absorbed into the circulation
descrive enalapril vs enalaprilat physicochemical properties
enalapril - inactive prodrug
- good absorption characteristics
- poor pharmacodynamic activity - ester group now too big to fit into active site pocket
enalaprilat - active drug
- poor absorption characteristics
- good pharmacodynamic activity
what are enalapril PK parameters
Dose: 2.5mg once daily
Log P = 0.7
Solubility = 0.213 mg/ml (requires formulation as salt)
Bioavailability: 60%
Plasma protein binding = 50-60% (enaliprilat)
VD = 0.7-1.7 L/kg (enaliprilat)
Half-life = 12 hours (enaliprilat)
Primary route of elimination = renal excretion (enaliprilat)
