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

Abstract Structure–activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H 1 -antihistamines. Reductions in p K a 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.