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video 8 of 9 in drug discovery 101 playlist

learning objectives
outline the lead optimization process
describe the role of activity data in lead optimization

From lead selection, we have a lead, actually a leads – a lead series. During lead optimization, the concept of optimization applies to the properties of the compounds. Which properties? I’ll group the four properties into four areas. Potency, which is the concentration at which the compound exerts its effect. A lower concentration is better and often corresponds to a lower dose for the final drug. Efficacy – the magnitude of the beneficial effect of the compound. ADME & pharmacokinetics (or PK) – These are properties that ultimate determine traits like the half-life, absorption, and excretion of a compound. In other words, how a drug gets in a patient, how long it stays, and how it gets out. Finally, safety – undesirable toxic effects of a compound. These are the key properties. How are these properties tested? – initially through in vitro assays and later with in vivo studies. Let’s see how this process works.

The process is highly iterative with feedback in each cycle. Let’s say that we start with the lead series and select a new analogue. We will perform many tests. These could be multiple in vitro assays or in vivo studies in preclinical species. We would then evaluate the activity data and how the compound performed. We would then consider the results in the context of the available SAR data. This data set would include the activity of other compounds as well as other information like x-ray data for the target. We would then make yet another new analogue, and the process would repeat. By repeatedly going through this feedback cycle, hopefully we can generate a compound that has adequate properties – potency, efficacy, PK, and safety – to become a clinical candidate for the discovery program.

Here is the same idea shown more visually. The original lead picked from the selected lead series is shown here as a single compound – a big red dot. Modifications to the lead involve making structural changes to the compound to give new analogues of the original lead. The black dots are new analogues. Some analogues will have poorer properties, and others will be better. Again, “properties” is a general idea – potency, efficacy, PK, and safety. Tradeoffs are common as sometimes one specific property may improve at the cost of another. It’s messy! One or more analogues may represent notable improvements and be considered a new lead. The preparation of more analogues may afford another improved lead. Eventually, properties may be improved to a degree that the preclinical data support an IND application so that the lead can be advanced into the clinic.