Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6

Structure–activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H1-antihistamines. Reductions in pKa via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.

Graphical abstractNear exclusive CYP2D6 metabolism in early lead 2a was addressed by reduction in pKa of the basic amine. Incorporation of a heteroaryl moiety or a β-fluoro substituent led to the identification of 8l, 8o, and 12f, with promising primary in vitro profiles and reduced biotransformation via CYP2D6.Figure optionsDownload full-size imageDownload as PowerPoint slide