Med Chem Part 4 Flashcards by amanda kastel

“Indolopyran acetic acid”

what is the drug?

etodolac

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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

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name 2 ways in which tolmectin and indomethacin are structurally similar

-2 ring systems are noncoplanar

-both contain acetic group

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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

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explain the selectivity of diclofenac

slightly more selective towards COX2 than COX1**
but still considered nonselective

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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

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how is diclofenac non coplanar?

the ortho Cl groups cause steric clash/hindrance

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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

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ketorolac is mainly used as ______

an analgesic

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what is the structural relationship between tolmetin and ketorolac

when a alpha methyl groups is fused onto tolmetin, ketorolac is basically formed

very similar

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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

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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

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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

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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

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as mentioned, the S enantiomer of ibuprofen is more potent than R.
why?

in the R isomer, there is unfavorable steric clash with Tyr355

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explain the metabolism of ibuprofen

CYP2C9

hydroxylation of w, w1, w2 carbons of the para-isobutyl chain. this results in an INACTIVE alcohol metabolite

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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

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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

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how can you remember the structure ketoprofen and fenoprofen

ketoprofen = ketone
fenoprofen = phenoxy

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what is the only profen that is marketed as a pure enantiomer? which enantiomer is it?

NAPOROXEN

marketed as pure S enantiomer

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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

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true or false

naproxen is the only profen marketed as a pure enantiomer
all the others are racemic mixtures

TRUE

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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