Introducing a nitrile in the place of less polar substituents is a fairly common approach to reducing lipophilicity in a lead molecule but in this review from the MedChem group at Pfizer the associated benefits of specifically the aromatic chloride to nitrile transformation are explored in some depth. They initially highlight the ubiquity of aromatic chlorides in hits from high throughput screens and speculate on the reasons for this, particularly with respect to the relative paucity of nitrile containing hits in similar screens. Next they highlight the similarities and differences between chloro- and nitrile-substituted aromatics and make the case (by analysis of a matched pair data set) that, whilst there will always be exceptions, the substitution from chloro to nitrile generally results in improved lipophilic efficiency (LiPE) and hence a likely improvement in drug-like properties (e.g. improved metabolic stability in microsomes is presented as one such outcome).
The authors also highlight recent developments in synthetic chemistry which have made aromatic nitriles much more readily accessible, in particular by direct metal-catalysed cyanation of aromatic chlorides themselves. Well worth a read and certainly, given the key benefits demonstrated and the comparative ease of synthesis using modern methods, a transformation not to be ignored in any drug discovery programme.
Note: Another review published last year which makes for interesting reading looks at the role of the nitrile group in launched drugs and in advanced clinical candidates.