Understanding Our Love Affair with p-Chlorophenyl: Present Day Implications from Historical Biases of Reagent Selection

摘要

We report here an unexpectedly strong preference toward para substitution in phenyl rings within drug discovery programs. A population analysis of aromatic rings in various drug databases demonstrated that para substitution is favored over meta and ortho regioisomers, with p-chlorophenyl (p-ClPh) being one of the most predominant examples. We speculate that the frequency of p-ClPh is traced back to historical models of medicinal chemistry where para-substituted regioisomers were perhaps more easily accessed, and further reinforced by Topliss in 1972 that if Ph was active, the p-ClPh should be made because of ease of synthesis and hydrophobicity driven potency effects. On the basis of our analysis, the para bias has become useful conventional wisdom but perhaps so much so that a perception has been created that druglike space favors a linear aromatic structure. It is hoped this analysis will catalyze a new look at design of reagent databases and screening collections.