contrasting lead-like & drug-like compounds

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The goal of lead optimization is to finish with a compound with properties - efficacy, potency, PK, and safety - suitable for advancement into clinical trials. In short, we want to finish with a drug. We have previously discussed drug-like molecules in the context of drug-like space for oral drugs. These drug-like molecules had around 30 heavy atoms (30 atoms excluding hydrogen atoms) and have a molecular weight in the range of 400-450 depending on the identity of the 30 atoms. This definition of drug-like space came out in 1996. In 1997 Lipinski and co-workers published a set of criteria now known as Lipinski’s rules or the Rule of 5, which say that oral drugs should have a molecular weight of 500 or less, no more than 5 hydrogen bond donors, no more than 10 hydrogen bond acceptors, and a log P (a measure of lipophilicity) no higher than 5. A compound that breaks two or more of these “rules” is at high risk of having poor oral availability. These are all examples of physicochemical properties. These specific properties can predict oral absorption of a molecule. How are these relevant to lead optimization?
What happens during lead optimization? The properties of a lead are improved. One of those properties is potency. Potency is often increased by making the lead larger (adding functional groups) so that the lead will have more binding interactions with its target. Adding groups increases molecular weight. Often, adding groups will also increase the lipophilicity of compounds in the lead series. You might notice a problem. Increasing molecular weight and lipophilicity may help potency, but oral absorption may drop such that the drug is no longer sufficiently orally available. How can we minimize the chance that we will overshoot molecular weight or lipophilicity during lead optimization?
In order minimize oral absorption issues due to high molecular weight and lipophilicity during lead optimization, the discovery team will often prioritize leads that are lead-like rather than drug-like. On the left we have our drug-like criteria - Lipinski’s rules. On the right are criteria for lead-like compounds as reported by Teague and co-workers in 1999. Lead-like compounds have a lower molecular weight (less than 350 g/mol) and lower log P (less than 3). The idea is that by selecting lead-like leads with a lower molecular weight and log P leaves room for increases to both molecular weight and lipophilicity without immediately clashing with the suggested limits described by Lipinski. The tension between boosting potency with molecular weight and lipophilicity gains and maintaining satisfactory oral absorption is often a constant challenge during lead optimization. The discovery team will continuously balance these properties against each other throughout the lead optimization process.