Med Chem Part 4 Flashcards
“Indolopyran acetic acid”
what is the drug?
etodolac
true or false
the acetic acid group on Etodolac can be replaced with butanoic or propionic acid
FALSE - must be acetic acid
others are inactive
name 2 ways in which tolmectin and indomethacin are structurally similar
-2 ring systems are noncoplanar
-both contain acetic group
what is an important consideration of phase 1 metabolites of NSAIDS**
they are almost always INACTIVE as COX inhibitors
this is because the purpose of phase 1 metabolism is to add a polar functional group. This will make the NSAID too polar to be able to bind to COX - must be a lipophilic acid
explain the selectivity of diclofenac
slightly more selective towards COX2 than COX1**
but still considered nonselective
how is diclofenac a concern
HEPATOTOXICITY CONCERN
CYP3A4 metabolism produces a 1,4 iminoquinone, highly reactive and electrophilic intermediate. can bind to hepato proteins and cause toxicity
how is diclofenac non coplanar?
the ortho Cl groups cause steric clash/hindrance
as mentioned, diclofenac has a hepatotoxicity concern due to the reactive metabolite that can be formed and its binding to hepato proteins
explain further the chemistry that allows this binding to happen
the 2 ortho Cl groups increase the electrophilic character of the meta positions on the halogen-containing ring
the ring is thus vulnerable to attack by nucleophilic cysteine residues of hepato proteins
ketorolac is mainly used as ______
an analgesic
what is the structural relationship between tolmetin and ketorolac
when a alpha methyl groups is fused onto tolmetin, ketorolac is basically formed
very similar
what is the underlying difference in structure between profens and phenacs?
what is the result of this change?
phenacs have an H attached to the center carbon, will profens have a CH3
profens have a chiral center - have r and s enantiomers
as mentioned, profens have a CH3 on alkanoic acid rather than an H. this leads to increased activity and decreased hepatotoxicity
what else can you conclude from this CH3 replacing H?
there is now a chiral center!
therefore, profens have both R and S enantiomers
as mentioned, profens have both R and S enantiomers
is there any difference in potency in case of Ibuprofen?
YES
(S) isomer is more potent than the (R) isomer
however, it is marketed as a racemic micture
ibufenac vs ibuprofen
ibufenac has a H attached to alkanoic acid instead of a methyl group.
this CH3 results in increased activity and decreased hepatotoxicity!! therefore, ibuprofen is more active and less hepatotoxic than ibufenac
as mentioned, the S enantiomer of ibuprofen is more potent than R.
why?
in the R isomer, there is unfavorable steric clash with Tyr355
explain the metabolism of ibuprofen
CYP2C9
hydroxylation of w, w1, w2 carbons of the para-isobutyl chain. this results in an INACTIVE alcohol metabolite
true or false
the metabolite of ibuprofen is inactive
TRUE
hydroxylation of w, w1, and w2 carbons into more polar ALCOHOL
too polar to still interact with COX active site
important:
differentiate and show similarities between the SAR of fenoprofen and ketoprofen
the only difference between the 2 is that fenoprofen has -O- between the 2 rings and ketoprofen has a carbonyl
for both, the phenyl ring with the -o- or carbonyl must be META TO THE PROPIONIC ACID
moving to ortho or para leads to decreased activity because it cannot fit in the binding site of COX1
how can you remember the structure ketoprofen and fenoprofen
ketoprofen = ketone
fenoprofen = phenoxy
what is the only profen that is marketed as a pure enantiomer? which enantiomer is it?
NAPOROXEN
marketed as pure S enantiomer
why is S enantiomer of naproxen more effective
the CH3 fits in the hydrophobic cleft adjacent to Val349
in the R enantiomer, there is a steric clash with Tyr355
CH3 must be pointing down - as in the S enantiomer
true or false
naproxen is the only profen marketed as a pure enantiomer
all the others are racemic mixtures
TRUE
true or false
naproxen is not a profen
false - it is
name a heteroaryl propionic acid that is NOT a profen
what is the difference?
Oxaprozin
the propionic acid chain is BRANCHED, while the chain for the profens is straight
what is an important factor of ALL lipophilic acidic NSAIDS that makes them prone to drug-drug interactions
they are greater than 90% bound to albumin (plasma protein)
explain the interaction that exists between warfarin and ibuprofen
both are highly protein bound and thus compete for the same binding sites
warfarin is much more potent than ibuprofen. therefore, ibuprofen is more likely to bind to the albumin sites. this will cause increased levels of warfarin in the blood and increase the risk of bleeding
WHY are all NSAID’s highly albumin/plasma protein bound?
albumin, like COX also has a hydrophobic “pocket” and a charge
structure is similar - will want to bind both
the fenamic acid class of NSAIDS is a derivative of what?
salicylic acid
what are the 2 drugs in the fenamic acid family
Mefenamic Acid
Meclofenamic Acid
how is the fenamic acid class derived from salicylic acid
-O- is replaced with the bioisostere -NH-
N-aryl anthranilic acid like
true or false
the NH in the fenamic acid class is ESSENTIAL for activity
true
where is substitution favored in the fenamic acid family?
what other drug is this similar to?
substitution of groups that will allow for non coplanar formation (such as Cl) are preferred, only at ORTHO positions to NH2
similar to Diclofenac
true or false
in the fenamic acid class, substitutions on the anthranilic acid ring have no effect on activity
FALSE - reduced activity
in the fenamic acid family, the COOH and the NH2 must be _________ to each other
how can you remember this?
ORTHO
same with aspirin - OH and COOH must be ortho
which is more potent and why - Mefenamic acid or Meclofenamic acid?
which is more lipophilic?
Meclofenamic acid
has 2 Cl that are ORTHO to the NH2 — allows for more non coplanar behavior
CH3 and Cl contribute equally to lipophilicity. however, meclofenamic acid has 2 Cl and CH3 while mefenamic acid only has 2 CH3. therefore, meclofenamic acid is more lipophilic
what are oxicams?
the new ENOLIC acid class of NSAIDS
NON carboxylic acid NSAIDS
what was the purpose of creating oxicams?
attempt at having less GI irritation which is so commonly associated with NSAIDS
how? -> no carboxylic acid group!
in the structure of oxicams, is a secondary or tertiary carboxamide more potent?
why?
secondary amides are more potent
this is because that H on nitrogen is needed to form tautomer B through resonance
what is the only functional group in oxicams that is acidic
hydroxyl group
true or false
carboxamides are neutral
true
are sulfonamides acidic?
it depends
if tertiary no - no proton
if primary or secondary then yes
how is it that the OH on oxicam is acidic
through RESONANCE - tautomerization
what is the pka of oxicams?
4-6
aside from the OH group, what else adds acidic character to oxicams?
a nitrogen containing heteroaromatic ring (at R)
like thiazole or pyridine
name 2 oxicams
piroxicam and meloxicam
explain the difference in structure between piroxicam and meloxicam
both have oxicam as base
piroxicam has a pyridine attached at R position, while meloxicam has a thiazole with a methyl group meta to attachment to oxicam
do oxicams show any COX selectiviity?
yes - meloxicam more selective to COX2
true or false
meloxicam is more selective to COX1
false - more selective to COX2
Nabumetone is similar in structure to what other drug?
how?
naproxen
the active metabolite of nabumetone (6-MNA) has an acetic acid while naproxen has a PROPionic acid
by which mechanism is the prodrug nabumetone converted into its active metabolite?
what is the name of this active metabolite?
oxidation on butanone side chain through CYP1A2
6-MNA (6-methoxy naphthalene acetic acid)
true or false
nabumetone is an acidic prodrug
FALSE
NON ACIDIC
remember - it is not an acid. does not cause GI irritation
becomes acidic (acetic) upon metabolism by CYP1A2
can the methoxy group on nabumetone be changed?
is it retained in the active molecule
can be changed to methyl or chlorine
methoxy is retained in the active molecule (6-MNA)
can the ketone on nabumetone be changed?
can be changed to dioxolane to retain activity
changing to oxime REDUCES activity
what happens if the C6 methoxy is removed from the structure of nabumetone (and not replaced with CH3 or Cl)
reduction in activity
does nabumetone cause Gi irritation? through which mechanism(s)
NO
it is a NONACIDIC PRODRUG
primary mechanism doesnt exist - no acid to irritate
secondary mechanism - it is a PRODRUG – not active when passing through GI – therefore, PGE1 prostaglandin synthesis is not inhibited and the protections of the stomach produced by prostaglandins remain
how is it that nabumetone is not active but 6-MNA is?
must have an acidic group to interact with COX
nabumetone is not acidic, but becomes acidic upon oxidation of butanone side chain by CYP1A2 to acetic acid
