Lecture #4 Flashcards
what is lead optimization?
represented by a sequence of interactive processes useful in order to improve the quality and reduce liabilities present in the leads identified → core of drug discovery - worth it to prolong this phase to discovery the test possible class of molecules
what animal do humans share high homology of NK1 receptor with?
gerbils - no homology or only partial with rats
in the search for a NK1 receptor antagonist, what did they discover about the majority of molecules once it had progressed to a 7 day TOX study in marmoset?
the majority of the molecules were hepatotoxic
what is the probability for success of small molecules in the target identification phase?
80%
what is the probability for success of small molecules in the HIT id phase?
medium-high and depends on the tractability of the target
how does the tractability of the target effect the probability for success in the HIT id phase?
means that the molecule is managed in terms of synthetic modification but it is fundamental also that the drug should be tractable so that it is able to be recognized in a chemical entity → is not equal among biological targets
what is the probability for success of small molecules in the lead ID phase?
~75%
what is the probability for success of small molecules in the LOP phase?
~85%
what is the probability for success of small molecules in the early development phase?
69% → depends on the quality of the molecule and has to be characterized by one month studies in both rodents and primates
what is the probability for success of small molecules in the FTIH phase?
63.2%
what is the probability for success of small molecules in the clinical efficacy (phase II)?
30.7%
one of the objectives today is to put in place “fast to kill projects”, what does this mean?
manage to understand the project associated with the highest probability of success, and manage to kill those projects not having the probability adequate for reaching candidate selection in order to devote resources to the most successful projects
when is the real validation of the target achieved?
phase II
in phase III what are the lead optimization strategies run on?
a working hypothesis → wen you are dealing with a specific issue, understanding the basic working hypothesis allows you to obtain the objective design
what is a biological molecule?
a medicine that contains one or more active substances made by or derived from a biological source ( vaccines, gene therapies, immunotherapies, stem cells, fusion proteins, mAbs, etc.)
why is the probability of success higher in biologics (particularly mAbs) than in small molecules?
due to the better tolerability of these compounds
what two areas are monoclonal antibodies used the most?
cancer and autoimmune diseases
what is the difference in molecular weight between small molecules and biologics?
small: low mw (<1KDa)
biologic: large mw (1-200 KDa)
describe the specificity needed for biologic molecules:
have to be specific and with a high affinity, in the order of picomolar - for the target respect small molecules that typically recognize a target in the order of nanomolar activity
describe the difference in permeability between small molecules and biologics:
it is high for small molecules that can free-distribute in tissues through systemic circulation
it is low for biologics because there are difficulties in crossing the membranes and so the distribution in the tissues (though blood and lymphatic circulation) is low → BUT the low distribution in tissues and the high specificity for the target of biologic molecules confer high tolerability
what is the problem for potential toxicity related to biologics due to?
immunogenicity: where the immune system responds and producing anti-drug antibodies is not something present in small molecules
what is the target of Adalimumab?
a TNF-⍺ in which there is abundant inflammatory cytokines in synovial fluids of the patients joints and it is responsible for the onset of rheumatoid arthritis
how does Adalimumab work?
it blocks the TNF-⍺ binding it non-covalently and proving its pro-inflammatory mediated actions
what disease is Adalimumab used to treat?
rheumatoid arthritis
