Cambridge MedChem Consulting

Bioisosteric Replacements

Carbonyl Replacements

Urea replacements

Ketone replacements

An interesting paper by Wuitschik et al looks at oxetanes as replacements for carbonyl and how they might influence physicochemical properties, whilst a variety of different structures are compared I’ve just pulled out the data for 4-substituted piperidines. Whilst the influence on pKa is intermediate between piperidine and the corresponding 4-piperidone the more polar oxetane means that the resulting LogD is actually lower. This could be useful if trying to reduce HERG, of CYP activity.


Intrinsic molar solubility (Eºmol/L) of the neutral base, obtained from the experimental thermodynamic solubility in 50 mM phosphate buffer at pH 9.9 and 22.5 ( 1 C, corrected for pKa and rounded to 2 significant digits. Pseudo-first-order rate constants, in min-1/(mg/EºL)protein, of intrinsic clearance, measured in human (h) and mouse (m) liver microsomes. Amine basicity in H2O measured spectrophotometrically at 24 C.

J. Med. Chem., 2010, 53 (8), pp 3227–3246 DOI

3-Hydroxyoxetanes have also been investigated as carboxylic acid bioisosteres.

In the X-ray structure of aromatase Ser478 is part of a water-mediated network of hydrogen bonding, enabling the interaction between aromatase and the C3-keto oxygen of androstenedione, McNulty et al DOI were able to use an aryl halide as a bioisosteric mimic for the cyclohexenone.


Last Update 23 July 2017