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
