Human dose prediction is so central to the way I think as a medicinal chemist. It’s the master variable. There’s no cheating it. I despise artificial screening cascade “gates” on projects. These are constructs put in place by people who are trying to control the flow of compounds to various assays to prevent those assays from having their capacity overwhelmed. That’s logistical, but not necessarily logical.
Who cares if the potency assay has a gate of IC50 < 10 nM? I can easily find you a dozen of those compounds that have zero oral exposure and will be dead on arrival. I can also probably find you a bunch of compounds with an IC50 of 100 nM that have excellent oral exposure and the legs to continue advancing. Historically, before our discipline became laser-focused on potency, the average potency of a drug molecule against its target (if the target was even known!) was on the order of 1 uM. That’s right - micromolar. We used to win the day on PK.
Anyway, point being for this tweetorial: potency and PK (and a bunch of other stuff) come together in a human dose prediction. If any of the underlying variables is in bad shape, the human dose will be too. It’s a far more useful framework for thinking about compound optimization than traditional, linear screening cascades that are all-too-prevalent in the pharmaceutical industry.
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