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

✍ Scribed by Charles Huang; Wilna J. Moree; Said Zamani-Kord; Bin-Feng Li; Fabio C. Tucci; Siobhan Malany; Jianyun Wen; Hua Wang; Samuel R.J. Hoare; Chun Yang; Ajay Madan; Paul D. Crowe; Graham Beaton

• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 930 KB
• Volume: 21
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.12.053

✦ Synopsis

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H 1 -antihistamines. Reductions in pK a via incorporation of a b-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.