Understanding Our Love Affair
with <i>p</i>‑Chlorophenyl: Present Day Implications
from Historical Biases
of Reagent Selection
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Abstract
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 <i>p</i>-chlorophenyl (<i>p</i>-ClPh) being one of the
most predominant examples. We speculate that the frequency of <i>p</i>-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 <i>p</i>-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