Mono‐ and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties
Kostiantyn P. Melnykov, Kostiantyn Nazar, Oleh Smyrnov, Artem Skreminskyi, Serhii Pavlenko, Oleksii Klymenko‐Ulianov, Svitlana V. Shishkina, Dmitriy M. Volochnyuk, Oleksandr O. Grygorenko
Abstract
Abstract A comprehensive study of physicochemical properties (p K a , Log P , and intrinsic microsomal clearance) within the series of mono‐ and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both p K a and Log P values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of “Janus face” (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis‐3,5‐difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3‐difluoroazetidine derivative). According to p K a – Log P plots, the title compounds provide a valuable extension of the fluorine‐containing (e. g., fluoroalkyl‐substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.