Drug Development Flashcards
What is a DRUG LEAD?
A compound with a required biological response.
Give problems with drug leads.
Too slow/fast non-specific target insoluble poor metabolism side effects toxicity difficult synthesis
Cheimcal modification stratergies 1: Simplification- remove non-essential parts to improve target --- and remove ---/---. Pharmacophore for cocaine and procaine: The important --- groups are --- The unnecessary --- group s removed. The complex --- system is removed. Also a need to remove --- centres. Identify the more potent --- and refine the ---.
specificity side-efffects binding retained ester ring asymmetric enantiomer synthesis
Structure rigidification:
Used to limit the number of —
incorporate adjacent groups to hinder —
incorporate a — substituent on to a —
Put the functional group into a — system
conformations rotation bulky ring ring
Conversion of hydroxyl to ,ethyl ether or ester:
This alters - bonding, —/—, interactions between drug and —, activity and —
H
water solubility
target
bioavailability
Effects of the conversion of amine to amide:
Amines are more/less basic than amides?
The ionic activity is removed if it is —
This changes the bonding to the —, and also changes the – and the —
more protonated receptor activity bioavailability
Conversion of ketone to Alcohol:
The — is still present, but it is — different, Alcohols have a — bonding shape, and ketones have a — bonding shape.
This may change the —/—.
H-bonding structurally tetrahedral planar bonding site
Removal of double bonds:
This changes the shape from planar to —
It reduces — interactions with the — pocket of the —
non-planar
van der Waals
hydrophobic
receptor
Alteration of alkyl size and introduction of unsaturation:
Branching, multiple bonds, aromatic rings have more — interactions with the —/— than —/—.
This may alter the — and — with a receptor, or alter the activity of the —
VDW binding region alkyl chains docking binding enzyme
Use of a steric shield:
This is where a — group or two —/— are added to prevent metabolic — or —
bulky
adjacent substituents
hydrolysis
oxidation
Altering chain length:
Chain extension may improve —/— or find secondary —/—. Raising n in (CH2)n will assist —/—, but in general, when n>6 , this generally prevents —/—.
primary bonding
bonding sites
membrane transport
aqueous transport
Rings and substituents:
Extra rings or — are sometimes used to find another —/—
Expansion + contraction of ring alters relative position of —/—
heteroatoms
binding region
binding groups
Configuration change at carbon:
Binding site may be sensitive to the — environment.
The Ea of of enzymic — may differ
enantiomers may — in vivo
chiral
intermediates
interconvert
Bioisosteres: These are atoms or groups of atoms which are closely related in --- or --- which can be --- in a compound to produce similar --- properties. F as an isostere of H: This has an effect on --- and --- The - withdrawing - affects its neighbours. The altered -- changes the preferred --- There is an improved metabolic --- The metabolically active site is ---
size charge exchanged biological pKa reactivity e- F H-bonding conformation stability blocked
Non-classical bioisosteres:
These are structurally —, there is usually a different number of — and exhibit different — and — properties
distinct
atoms
steric
electronic
What is a prodrug?
A pharmacologically inactive drug that can be converted to an active drug metabolic process in vivo.
Latentiation:
Where the bioactivity is latent.
Prodrugs should be readily — by an —, or react readily —
It should be less — than, and much less — than the active drug. It should not introduce toxic —
Hard drugs are compunds which…
Soft drugs are compounds which
metabolised enzyme biochemically toxic active metabolites are not susceptible to metabolism are readily metabolised.
Prodrug examples:
The most common strategy is to make an —
From a — and a —
It is converted to the — in vivo by —
Other groups that undergo phase I metabolism includes the — of the compound.
The antibacterial prodrug prontosil is converted to an active — by —/—
ester alcohol carboxylic acid acid esterases deamination sulphonamide azo reduction
Prodrug examples- making it ionic:
This raises the —/— but leads to poorer — transport
The —/— reacts with a base to give an —/—
The secondary amine is generally more/less polar than the primary, it can be derivatized to a —/—/—.
Protonated tertiary amines are less — and have weaker — bonding to the target
water solubility membrane carboxylic acid ionic salt less phopsphate disodium salt basic ionic
Making polar drugs for carrier proteins:
L-Dopa has ability to cross the —/— barrier.
then — remove the — group so that dopamine can be delivered after the — has been crossed.
blood-brain
decarboxylases
CO2H
membrane
Alkylate to improve membrane permeability:
Eg. the prodrug antihistamine terfenadine.
Metabolised in the — by — to convert one — to the active —/—
liver
cytochrome P450
CH3
carboxylic acid
Prodrug strategies summary Esterify a ---/---, or other groups undergoing a ---/---/--- Make --- drugs for --- proteins Alkylate to improve ---/--- Prolong activity by (2) Target the site by --- and --- \:
carboxylic acid phase 1 metabolism polar carrier membrane permeability ring addition or longer chain addition pH, enzyme
Sleeping drugs:
— prodrug activated by an — agent
Main research in development of —/—
— agents collect in —
inactive external photodynamic therapy photosensitive cells.
