med chem Flashcards
nucleophiles
. electron rich, -ve charge/long pair
. hard nucleophile: small, electronegative, basic, low HOMO
. soft nucleophile: large, polarisable outer shell, not basic, high HOMO
electrophile
. electron deficient
. hard: +ve charge localised, not spread out over large area
. soft: +ve charge delocalised, spread over large area
requirements for delocalisation
1) planar
2) sp2
3) conjugated
4) Huckel’s rule: 4n+2 e-
why are reactive metabolites not good
1) inhibit metabolising enzymes
2) induce ADR
3) damage DNA
components of P450
1) heme
- large, accommodate to lipophilic molecules
2) flavoprotein
- accept e- from NADPH and transfer e- to p450
3) phosphilipid matrix
- facilitate electron transfer
electron cycle for transferring from NADPH to p450
- draw out
P450 catalytic cycle
1) R-H bind, displace H2O
2) change in conformation, Fe III unstable
3) accept 1st e- from Fe III, change to Fe II
4) Fe II bind to O2 -> peroxide radical (-O-O.)
5) accept second e- to form peroxide anion (-O-O-), have to happen fast if not can leave as superoxide
6) H+ bind, form Fe-O-OH
7) displacement of water, activate water (O+), resonance structure of O. and Fe IV forms
8) oxygen rebound, back to normal
when does reactive metabolite formp450 catalytic cycle?
1) reduction
- more reducible substrate can be reduced instead
- stepwise transfer of e- forms radical
2) oxidation
- stepwise transfer of e- form radicle
- superoxide released instead
3) O2 rebound
names of position on the ring
ortho, meta, para !!!
ways o-acyl-glucuronides can change
1) hydrolysis
- basically hydrolyse and release glucuronic acid
- CES 1/2
- beta-glucuronidases
- serum albumin, alkaline pH
- acyl-glucuronide > 500 MW: enterohepatic cycling, excreted in bile & hydrolysed by beta-glucuronide, reabsorbed, increase drug exposure
2) intramolecular arrangement
- move to C1, C2, C3 ,C4
- C3, C4: RM cuz hemiacetal structure, can open up ring to expose reactive acetaldehyde
3) transacylation
- transfer acyl group to protein, protein adduct not very immunogenic
- BUT transfer releases glucuronic acid which is the same as ^
formation of RM from amine glucuronide
. acidic conditions (urine)
- hydrolysis to produce nitreunium ion (N-)
- electrophilic, can react with macromolecules
methods to evaluate bioactivation potential (X3)
1) experimental design
2) daily dosage
3) Structural alerts
methods to evaluate bioactivation potential - experimental design
1) covalent binding with radioactive drug
- provide quantitative results, not structural
- in vitro/vivo
2) metabolite identification
- detect stable conjugates of electrophilic metabolite & GSH
methods to evaluate bioactivation potential - daily dosage
- lower chance of AE if daily dose < 20 mg
methods to evaluate bioactivation potential - structural alerts
- toxicophores
- structural alert -> RM -> structural alert
- done by visual inspection/software
. SA available
- AE: expected
- no AE: low dose drug, other site metabolised instead of AE, not metabolised to great extent
. no SA
- AE: SA not discovered yet, other mechanisms involved (mitochondrial toxicity, inhibit bile salt export pump (BSEP))
phase 2 conjugation reactions
1) glucuronidation
- COOH, OH, NH2, SH
- glucuronic acid
- smooth ER
2) sulfation
- OH, NH2
- sulfate group (SO42-)
- cytosol
3) acetylation
- NH2
- attach acetyl group (Draw)
- cytosol
4) glutathione conjugation
- electrophilic centres
- glutathione acid
- cytosol, smooth ER
5) methylation
- SH, NH, OH
- methyl group
- cytosol
6) amino acid conjugation
- COOH
- glycine, glutamic acid
- mitochondria
types of prodrugs
1) carrier-linked prodrugs
- basically attach promoiety through covalent bonds (amide, ester, carboesterase)
2) bioprecurosr
- no promoiety
- oxidation, reduction, rearrangement
- site specific
ideal characteristics for prodrugs
1) stability, won’t be prematurely released
2) balance of lipophilicity & solubility
3) conversion & absorption at site of action
4) innocuous product that doesn’t cause AE
prodrugs that increase water solubility for parenteral drugs
1) add succinate acid
- to -OH
- provide terminal OH that increases water solubility
2) add phosphate
- to -OH
- if not -OH can make one there
- extra linkage lost as acetaldehyde
prodrugs that increase water solubility for oral drugs
requirements for these prodrugs
1) soluble in intestinal fluid
2) enzymes required available at intestinal region
3) conversion & absorption at same site
. must have -OH for phosphate group
prodrug to improve passible permeability
- ensure balance between lipophilicity & solubility there
- requirements
1) log p < 5
2) MW < 500
3) solubility > 400
prodrugs for carrier mediated active transport
. basically make full use of promoieties that can bind to receptor to be passed through
. for drugs that cannot use passive permeability cuz toxic for concentration required for concentration gradient
prodrugs to improve metabolic stability
. skip first pass vibes
