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

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

doi:10.1016/j.bmcl.2010.12.053

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

Bioorg Med Chem Lett. 2011 Feb 1;21(3):947-51. doi: 10.1016/j.bmcl.2010.12.053. Epub 2010 Dec 16.

Authors

Charles Huang¹, 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

Affiliation

¹ Neurocrine Biosciences, San Diego, CA 92130, USA.

PMID: 21232954
DOI: 10.1016/j.bmcl.2010.12.053

Abstract

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 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.

MeSH terms

Biotransformation
Cytochrome P-450 CYP2D6 / chemistry*
Cytochrome P-450 CYP2D6 / metabolism
Histamine H1 Antagonists / chemical synthesis
Histamine H1 Antagonists / chemistry*
Histamine H1 Antagonists / pharmacokinetics
Indenes / chemical synthesis
Indenes / chemistry*
Indenes / pharmacokinetics
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / pharmacokinetics
Receptors, Histamine H1 / chemistry*
Receptors, Histamine H1 / metabolism
Structure-Activity Relationship

Substances

Histamine H1 Antagonists
Indenes
Pyrazines
Receptors, Histamine H1
Cytochrome P-450 CYP2D6