Thomas DiPuma

Several influential studies published around the turn of the millennium reported that advancing a lead compound to a drug tended to involve certain predictable changes in molecular properties, most notably marked increases in molecular weight (MW) and in lipophilicity. To assess how lead optimization practices have changed over the past 20 years, we examined oral drugs approved during 2020-2023 and their corresponding lead compounds with respect to their molecular properties. As well as comparing property averages, we analyzed the changes introduced in each individual drug discovery program to directly assess the trends that characterize the modern lead-to-drug process. We found that changes in MW from lead to drug are substantially smaller than in the older studies, with a median mass change corresponding to addition of just a single heavy atom, and cLogP is now slightly more likely to decrease than to become greater. Thus, the notion that lead optimization tends to involve making the compound ‘bigger and greasier’ no longer applies. Rather, approaches have been found to refine compound potency and selectivity, and to eliminate ADME liabilities, without adding substantial mass or overly relying on the hydrophobic effect as a driver of binding. One such tactic may be avoiding addition of aromatic groups during lead optimization, coupled with a tendency to favor heterocycles over aromatic carbocycles. Overall, our results imply that it may no longer be useful to think of ‘lead-like’ and ‘drug-like’ compounds as occupying distinct property space.

Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d bears an aminopyridine amide with an IC₅₀ of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog 7q has an IC₅₀ of 18.8 µM, with potency residing in the (R)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor (R)-7q with T_m = 50.2 °C and a K_i of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions.