Omeprazole
- Prodrug that rearranges into an active achiral drug; protonated at the most basic N in the stomach via covalent modification (do not protonate at NH bc breaks aromaticity)
- Aromatic at beginning then intramolecular rxn makes it non-aromatic, but reestablished in active compound
- N attacks S (bonded to O) (kicks off OH) and reestablish aromaticity
- Activates sulfur as electrophile, making active molecule
Omeprazole -> Patent
Prodrug is chiral, active species is chiral
- Omeprazole has 2 enantiomers (other is esomeprazole)
- When omeprazole (racemic mixture) lost patent protection, the drug company decided to use the S enantiomer that was optically pure (more potent) aka less side effects; changed name to esomeprazole
- Single enantiomer crucial in drug development
- Achiral version plays role in specific recognition of drug and potentially less side effects
Covalent Functionality
Typically the reactive part / electrophile is an unsaturated ketone or epoxide
Mustard Gas
Intramolecular SN2 Reaction
- Nitrogen forms epoxide with itself so that the nucleophile can attack it, kicks Cl off by alkylation and breaks ring first then reforms it
- N attacks C (kicks off Cl), forms epoxide, Nuc attacks epoxide, N attacks C (kicks off Cl again), Nuc attacks epoxide again, reforms ring
Aspirin
Acetylsalicylic acid inactivates COX enzyme, also acts as a covalent modifier, but has a reversible binding element to it
- Cox attaches to acetylsalicylic acid by breaking apart the ester region; cox region then gets cleaved off and is inactive -> blocks sensation of pain
Disulfram
- Covalent drug, disulfide region is reactive
- Disulfram targets acetaldehyde dehydrogenase
- Our body hates aldehydes so tries to covert it to AA through AD (but makes us feel hangover).
- Disulfram works by blocking the breakdown of alcohol in the body so that we do not feel negative effects -> used to treat chronic alcoholism
Where does disulfram inhibit acetaldehyde dehydrogenase? -> Attacks S-S bond in disulfram to form new S-S bond in acetaldehyde dehydrogenase, which makes it inactive
Ibrutnib
BTK Inhibitor
- Covalent adducts warhead close to reactor
- Reacts with an amino acid on enzyme
- Has a recognition of kinase element to bind to which acts as an inhibitor (reversible) then a covalent bond is formed (irreversible)
- Recognition element and reactive group = good selectivity of drug
- Warhead: the double bond next to the carbonyl
- Recognition: position warhead next cysteine so it can form a covalent bond
