Med Chem part 3 Flashcards by amanda kastel

explain WHY acetaminophen does not possess anti inflammatory and only antipyretic/analgesic activity

acetaminophen works by inhibiting Peroxidase activity, preventing the regeneration of the Tyr385 free radical to keep the prostaglandin synthesis cycle moving

HOWEVER, it can only do this in areas of LOW reactive oxygen species, and ROS is high in areas of inflammation, and therefore it cannot work there

tylenol has been showed to be stronger at inhibiting COX3 in the brain rather than COX2 and COX1

this leads to antipyretic and analagesic activity

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what does IC50 mean?

concentration of drug at which it inhibits the enzyme by 50%

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if the IC50 of a drug is low for a particular enzyme, what does this mean?

it is able to block the enzyme at low concentrations – more potent/more drawn to inhibit that enzyme

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true or false

the IC50 of tylenol for COX3 is higher than COX1

FALSE - LOWER

lower concentration is needed to inhibit COX3

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true or false

tylenol is a weak COX inhibitor

true

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in the structure of tylenol, what group is preferred at NH

acetyl group

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the structure of tylenol has an OH attached to a benzene ring.

explain how this could be changed, and what the result was found to be

when OH is etherified to OCH3 or O-isoPropyl, more side effects are produced than -OEthyl derivates and NO gain in pharmacologic activity

tylenol in which the OH has been etherified is phenacetin

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explain the relationship between phenacetin and tylenol, both structurally and functionally

phenacetin is structurally the same as tylenol, it just has been ehterified from OH to Oethyl (CH2CH3) also called ethoxy

functionally, phenacetin is converted into tylenol upon phase 1 metabolism - same pharmacologic activity

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what is the major pathway of acetaminophen metabolism?

in adults - glucuronidation (O-glucuronide)

in infants - sulfation (O-sulfate)

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when is the minor metabolism pathway of acetaminophen important?

in case of an overdose

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what is the name of the toxic metabolite produced from the minor pathway of acetaminophen metabolism?

NAPQI (N-acetylimidoquinone)

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true or false

NAPQI is a nucleophile

FALSE - electrophile
very reactive
has partial positive charges on carbons next to =O

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What are the enzymes that produce NAPQI

CYP2E1 and CYP3A4

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explain why it is not recommended to drink alcohol and take tylenol at the same time

alcohol induces CYP2E1, the same enzyme that produces the toxic and reactive tylenol metabolite - NAPQI

more of NAPQI may be produced, causing liver damage

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name the 3 fates of NAPQI

the endogenous way to clear it is by GSH (glutathione) conjugation. it is then renally excreted as mercapturic acid
An antidote, N-acetyl cysteine, can be administered. it will also be excreted as a mercapturic acid derivative
if these 2 pathways cannot handle the amount of NAPQI, it will covalently bind to hepatic proteins and create a toxic hepatic complex, causing hepatic necrosis and renal failure

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in GENERAL, what structures are used as antidotes for tylenol overdose?
name a specific antidote

-SH containing compounds

N-acetyl cysteine is one

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what is GSH

a tripeptide made of glutamic acid, cysteine, and glycine

a well known reducing molecule. used endogenously in cases of tylenol overdose

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how is GSH and N-acetyl cysteine able to detoxify NAPQI

cysteine binds and is able to take care of the highly reactive and electrodeficient carbon

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true or false

tylenol overdose is not common

FALSE - it is

so many OTC products contain tylenol without explicitly stating it

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recap - name 2 salicylic acid derivatives that are NSAIDS

aspirin
diflunisal

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ortho vs para vs meta

ortho - 2 subst next to each other
para - opposite sides
meta - 1,3 position

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what is an important SAR (structure activity relationship) of salicylic acid derviatives
(if this is done, the drug is inactive)

the OH and COOH must be ORTHO - NOT para or meta

otherwise, the drug is not active

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name 2 ways in which the potency of salicylic acid derivatives can be enhanced

Add a lipophilic group at C5 position (diflunisal)
Esterification of phenolic OH with acetic acid (aspirin)

salicylic acid derivatives (salicylates) inhibit COX in a __________- manner

what is the exception

competitive and reversible manner

exception is ASPIRIN - inhibition is pseudo irreversible

true or false all NSAIDS are competitive and reversible inhibitors of COX, with the exception of tylenol

FALSE - tylenol is not an NSAID answer is aspirin - pseudoirreversible inhibitor

what is the role of the carboxylate group in aspirin?

hydrophilic component - pulls proton from serine on COX this leaves an O on serine with a negative charge which quickly binds to an acetyl group on aspirin

chemical name for aspirin

acetylsalicylic acid

explain the mechanism of action of aspirin and include why its action is "pseudoirreversible"

an acetyl group binds covalently to serine on COX. after an acetyl group leaves aspirin, it becomes salicylic acid. this salicylic acid stays within the enzyme pocket and blocks the access of arachidonic acid however, this acetylated serine on cox is easily hydrolyzed and converted back to the unrestricted enzyme. this is why it is "pseudoirreversible" -- it COVALENTLY BINDS -- but does hydrolyze back easily

true or false the mechanism of aspirin occurs through an ionic bond

FALSE covalent bonding of acetyl group to an O on serine (but easily hydrolyzed back)

once an acetyl group from aspirin binds to serine in COX, what is left?

salicylic acid + inactivated acetylated COX1

explain how the name "aspirin" can help to determine its structure

spirin = salicylic acid A = acetyl its acetylated salicylic acid

as mentioned, aspirin works through acetylating serine on COX. which serine?

for COX1 - Ser530 for COX2 - Ser516

what is the largest class of NSAIDs

arylalkanoic acids

what 2 categories of drugs are part of Arylalkanoic acids?

phenacs and profens

explain how phenacs and profens differ and how they are similar (as far as structure)

they are both in the aryl alkanoic acid class however, the R group for phenacs is H and the R group for profens is CH3 this, phencs belong to aryl acetic acid class and profens to aryl propionic acid class.

can the aryl ring of aryl alkanoic acids be conjugated with another ring? explain

yes, but they must be noncoplanar to achieve maximum hydrophobic contact with COX -- necessary for binding

what is the structural relationship between indomethacin and sulindac

indomethacin has an indole group while sulindac has an indene group instead

true or false the indole ring in indomethacin is ESSENTIAL for activity

false bc indene ring of sulindac also is active

indomethacin has an N-benzoyl group. if it was replaced with _____, activity would be decreased

alkanoyl or arylalkanoyl groups

indomethacin has a chlorine group attached to N-benzoyl. what could chlorine be replaced with to still retain the activity of indomethacin? why?

F or CF3 electron withdrawing groups are desired at this para position

true or false the COOH group in Indomethacin is not important

FALSE - it is very important this is what is making the molecule a lipophilic ACID, and similar enough in structure to arachidonic acid to compete with it

how is it that aryl alkanoic acids all have an issue of GI irritation?

the presence of acid (COOH) alone irritates GI. additionally, the inhibition of COX in the GI mucosa has bad effects. this prevents the synthesis of prostaglandins that have cytoprotective functions. damage to the GI is possible

prostaglandins have cytoprotective functions in the GI which prostaglandin is mainly responsible for this protective role?

PGE1

which enantiomer of indomethacin is preferred and what is keeping it in this conformation? why is it important?

when the N-para-chlorobenzyl group is CIS to the methoxy ring this is due to steric hindrance of: -CH3 on carbon 2 -Hydrogen on carbon 7 on either side this is important because this steric hindrance makes either ring NON COPLANAR with each other - easier to bind to hydrophobic channel in COX

what drug is an isostere of indomethacin?

sulindac

name the 2 ways in which Indomethacin is metabolized when does it become inactive

CYP2C9 mediated O-demethylation (inactive) amide hydrolysis (inactive)

why was sulindac discovered?

bc indomethacin was associated with GI irritation Sulindac was discovered as a PRODRUG -- eliminates the secondary mechanism of GI irritation that occurs when the drug inhibits COX in the GI mucosa, and thus inhibiting production of PGE1, which has protective roles in the stomach

true or false sulindac is not associated with GI irritation

FALSE - it still is eliminated secondary mechanism, but still has a COOH group in its structure. primary mechanism of irritation still exists

true or false Sulindac is not an active drug

true it is an inactive prodrug

as far as structure, explain the difference between sulindac and its metabolite

sulindac itself is an INACTIVE polar sulfoxide. it is a prodrug its metabolite is an ACTIVE nonpolar sulfide

which isomer of sulindac is more potent and why?

Z (cis) isomer is more potent this was already established from indomethacin the 2 rings must be cis to each other to be NONCOPLANAR and more easily bind to COX

what enzyme converts Sulindac into its active metabolite? where? is this reaction reversible?

CYP/FMO system in the liver yes, it's reversible

true or false sulindac is analgous to indomethacin and they are isosteres

true

which has a longer half life -- sulindac or indomethacin? why?

SULINDAC (8hrs - Indomethacin is 4) as mentioned, Indomethacin has 2 methods of metabolism and inactivation: -O-dethylation at H3CO -Hydrolysis of amide however, in the structure of Sulindac, H3CO has been replaced with F which is VERY STABLE TO METABOLISM! therefore, it only has 1 method if metabolism/inactivation has opposed to 2