Auberson, Yves, Brocklehurst, Cara, Furegati, Markus, Koch, Guido, Decker, Andrea, Briard, Emmanuelle and Thomas, Fessard (2107) Improving non-specific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres. ChemMedChem : chemistry enabling drug discovery.

Abstract

Bicycloalkyl groups have previously been described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction in complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves solubility by at least 50-fold, and markedly decreases non-specific binding (NSB) as measured using CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits with regard to non-specific binding or solubility, whereas substitutions with cubane-1,4-diyl also showed an improvement in both parameters. These results confirm the potential advantages of both BCP and cubane groups as bioisosteric replacements for optimizing para-phenyl substituted molecules.

Item Type:	Article
Keywords:	non-specific binding • bicycloalkyl • bioisostere • imaging agent • liquid chromatography
Date Deposited:	23 May 2017 00:45
Last Modified:	23 May 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31764