For example, during the process of CNS lead optimization, compounds will be measured for potency, selectivity, CYP inhibition profile, solubility, BBB permeability, toxicity, etc. How are the compounds ranked based on these properties? If we set cutoff values for these properties, does NCE that meets all criteria gets to move into in vivo evaluation or it's OK for compounds that only meet several criteria like potency, BBB permeability etc?
Dear Chenxiao Tang
Goal of drug discovery and development is drug approval by authorities (FDA, EMA, HC etc.). Key element in case of new drugs applications is toxicity and safety. So my suggestion is highest ranks for toxicity, next toxicity safety parameters, and last permeability, potency, activity etc. Even if you find excellent molecule with high permeability potency and activity if selectivity, cross-reactivity or toxicity will not be acceptable then the molecule will never reach the real world.
Article Predicting Chemical Toxicity Effects Based on Chemical-Chemi...
https://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf
https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/non-clinical/non-clinical-toxicology
Hope it will be helpful
Best regards
Tomasz
My suggestion is that first of all you should take into consideration the parameters that determine efficacy (selectivity, potency, solubility, BBB permeability). Depending on your target, when you find few efficacious compounds, then the toxicity parameters can be taken care of by selecting among the chosen or by further modifications in the structure, to find the lead.
Efficacy is a very important aspect in CNS drugs, as the translation correlation from animal to human is very difficult in this class of drugs.
It's a decision which takes a lot of experience to decide which criteria should be acceptable up to particular level.
Relevant literature is attached, esp. Hitchcock (2008) will be helpful.
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