25 Years of Small-Molecule Optimization at Novartis: A Retrospective Analysis of Chemical Series Evolution

In the drug development process,
optimization of properties
and
biological activities of small molecules is an important task to obtain
drug candidates with optimal efficacy when first applied in subsequent
clinical studies. However, despite its importance, large-scale investigations
of the optimization process in early drug discovery are lacking, likely
due to the absence of historical records of different chemical series
used in past projects. Here, we report a retrospective reconstruction
of ∼3000 chemical series from the Novartis compound database,
which allows us to characterize the general properties of chemical
series as well as the time evolution of structural properties, ADMET
properties, and target activities. Our data-driven approach allows
us to substantiate common MedChem knowledge. We find that size, fraction
of sp3-hybridized carbon atoms (Fsp3), and the density of stereocenters tend to increase
during optimization, while the aromaticity of the compounds decreases.
On the ADMET side, solubility tends to increase and permeability decreases,
while safety-related properties tend to improve. Importantly, while
ligand efficiency decreases due to molecular growth over time, target
activities and lipophilic efficiency tend to improve. This emphasizes
the heavy-atom count and log D as important
parameters to monitor, especially as we further show that the decrease
in permeability can be explained with the increase in molecular size.
We highlight overlaps, shortcomings, and differences of the computationally
reconstructed chemical series compared to the series used in recent
internal drug discovery projects and investigate the relation to historical
projects.