Sixteen years ago, the fraction of sp 3 centers (Fsp 3 ) in a molecule was correlated with clinical progression, solubility, and promiscuity in Lovering’s “Escape from Flatland” papers. These trends captivated academia and industry alike, motivating a flurry of strategies to incorporate sp 3 carbons into targets for medicinal chemistry. Given this widespread impact, we performed a retrospective analysis on the small molecule portfolio of Merck & Co., Inc., Rahway, New Jersey, USA (hereinafter “MSD”). We probe how Fsp 3 changed with year of synthesis and target class from 2000 to 2024, and whether Fsp 3 impacted compound progression. To investigate explanations for these trends, we analyze Fsp 3 ’s influence on lipophilicity, permeability, solubility, and off-target potency and compare these findings with previous studies. Leveraging MSD’s compound collection (millions of small molecules), we provide further context for the originally reported correlations and novel insights into incorporating Fsp 3 effectively in future drug designs.
Garry et al. (Thu,) studied this question.