Some of the discussions that come up here around clinical attrition rates and compound properties prompts me to see how much we can agree on. So, are these propositions controversial, or not?
1. Too many drugs fail in clinical trials. We are having a great deal of trouble going on with these failure rates, given the expense involved.
2. A significant number of these failures are due to lack of efficacy - either none at all, or not enough.
2a. Fixing efficacy failures is hard, since it seems to require deeper knowledge, case-by-case, of disease mechanisms. As it stands, we get a significant amount of this knowledge from our drug failures themselves.
2b. Better target selection without such detailed knowledge is hard to come by. Good phenotypic assays are perhaps the only shortcut, but a good phenotypic assays are not easy to develop and validate.
3. Outside of efficacy, a significant number of clinical failures are also due to side effects/toxicity. These two factors (efficacy and tox) account for the great majority of compounds that drop out of the clinic.
3a. Fixing tox/side effect failures through detailed knowledge is perhaps hardest of all, since there are a huge number of possible mechanisms. There are far more ways for things to go wrong than there are for them to work correctly.
3b. But there are broad correlations between molecular structures and properties and the likelihood of toxicity. While not infallible, these correlations are strong enough to be useful, and we should be grateful for anything we can get that might diminish the possibility of later failure.
Example of such structural features are redox-active groups like nitros and quinones, which really are associated with trouble - not invariably, but enough to make you very cautious. More broadly, high logP values are also associated with trouble in development - not as strongly, but strong enough to be worth considering.
So, is everyone pretty much in agreement with these things? What I'm saying is that if you take a hundred aryl nitro compounds into development, versus a hundred that don't have such a group, the latter cohort of compounds will surely have a higher success rate. And if you take a hundred compounds with logP values of 1 to 3 into development, these will have a higher success rate than a hundred compounds, against the same targets, with logP of 4 to 6. Do we believe this, or not?