Theme 6 Lecture 20 Flashcards
p,se,ph,ph,saf,c can
What does lead optimisation involve?
It requires improving potency, selectivity, physicochemical properties, pharmacokinetics, and safety of a lead compound to create a clinical candidate
SLIDE 2
What is it about lead optimisation that reserchers are always questioning?
What different functional groups can they change or alter to lead to more potent and selective binding interactions.
Molecule activity
Where does lead optimisation focus?
It focuses on improving the metabolic activity and the physicohemical properties without altering the molecules activity.
IC50 and HERG
Explain what the candidate target drug profile is and what is contained
The functional IC50 is usually done in-vivo in an animal model
HERG must be greater than 10 to avoid toxicity.
What’s the difference between primary and secondary assays in lead optimisation?
Primary measues potency and selectivity whereas secondary measures potency and efficacy.
cellular environement(cytosol resides)
What environment do secondary assays mimic?
Secondary assays mimic the cellular environment where the cytosol resides
interact
How are assay systems developed to measure enzyme activity?
They measure the enzymes ability under normal conditions to interact with the drug.
What is a critical factor for a drug’s effectiveness in an assay system?
Before the drug can engage with the target enzyme it has to diffuse into the cytosol.
The assay must allow the correct conc of drug to bind and inhibit the enzyme.
GI, m/e,SOA,Conc, No se
What process must a drug undergo to be effective in vivo?
The drug must be absorbed in the GI tract, avoid rapid metabolism and excretion, reach the site of action with the appropriate concentration, and interact with the target enzyme to have a therapeutic effect without side effects.
POST, liver, p Blood
What concerns must be addressed when considering drug distribution and metabolism?
Post-absorption, the drug must navigate through the body, survive liver metabolism, and reach the peripheral bloodstream to bind to and inhibit the target enzyme.
What are the key targets in lead optimisation?
The key targets are selectivity/potency/efficacy
IC50, level of enzyme inhibition and assays.
Define potency, efficacy and selectivity
Conc required to have desired effect
Refers to the degree of the effect for the compound.
The ability for a compound to act on its target with having minimal effects on other biological targets.
Slide 12
Interpret this selctivity plot and explain which one is better NDD-713 or NDD-825
NDD-825 slightly better because even though they both have good selectivity NDD-825 has less off targets selectivity profile.
And the selective inhibition for beta 2 is small so the ratio of of beta 1/2 has a better elcectivity profile.
What physical and pharmaceutical properties are optimised alongside biological properties?
Good solubility, lipophilicity and permeability in parallel with biological properties.
Logs, sol-perm
Link between lip,sol and perm
Lipo is to do with LogP(normal drugs) LogD (ionised drug)
Sol influenced by Lipo(functional groups and physiochemical properties)
A compound must be in sol to be perm
Perm influenced by both above, has to be lipohilic enough to permeate cell membranes and hydrophlic enough to be soluble
