In early drug development, candidate compounds undergo testing in in-vivo animal safety models. The results of these are usually written up in text documents, and not usually broken up into data points to be loaded onto a database, for example. The drug discovery chemists of this bucket list paper took these “raw” text documents and entered the results into spreadsheets to allow study against the chemical properties of the drug candidates – this itself is pretty heroic. A complication of any analysis involving in-vivo data is the dose / concentration of compound in blood will be different from study to study. For statistical rigour, the group chose the 10uM Total Drug Threshold as there was an even number of “clean” versus “toxic” outcomes for the compounds studied. From this there came a ‘medicinal chemistry rule’: low-ClogP(<3)/high-TPSA(>75) are approximately 2.5 times more likely to be clean as to be toxic. However, the authors came to realise they had missed something in the analysis, and subsequently referred to it during conference talks. At the 1uM threshold (Figure 3 above) the majority of the compounds were clean. So highly potent compounds, with good bio-availability, enables low dosing is the best route to non-toxic results pre-clinically, irrespective of properties.
Physiochemical drug properties associated with in vivo toxicological outcomes
#BucketListPapers #DrugDiscovery #MedicinalChemistry #BeTheBestChemistYouCanBe