Log P as a tool in intramolecular hydrogen bond considerations.

ABSTRACT

Intramolecular hydrogen bonding (IMHB) considerations are gaining relevance in drug discovery and a molecular descriptor which can predict very early the capacity of a compound to form IMHB is needed to speed up the optimization process of drug candidates. Although log Poct is largely used for optimization purposes, in this paper we firstly use the Block Relevance (BR) analysis to theoretically show how log Poct is not a convenient choice to assess IMHB properties of candidates. Then we discuss the limits of log Poct and introduce Δlog Poct-tol, i.e. the difference between log Poct and log Ptol (the logarithm of the partition coefficient in the toluene/water system). Finally, we provided some examples also including bRo5 protease inhibitors, to clarify how to interpret Δlog Poct-tol values.