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 com...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-02, Vol.21 (3), p.947-951
Hauptverfasser:	Huang, Charles, Moree, Wilna J, Zamani-Kord, Said, Li, Bin-Feng, Tucci, Fabio C, Malany, Siobhan, Wen, Jianyun, Wang, Hua, Hoare, Samuel R.J, Yang, Chun, Madan, Ajay, Crowe, Paul D, Beaton, Graham
Format:	Artikel
Sprache:	eng
Schlagworte:	Biological and medical sciences Biotransformation Cytochrome P-450 CYP2D6 - chemistry Cytochrome P-450 CYP2D6 - metabolism Histamine and antagonists. Allergy Histamine H1 Antagonists - chemical synthesis Histamine H1 Antagonists - chemistry Histamine H1 Antagonists - pharmacokinetics Indenes - chemical synthesis Indenes - chemistry Indenes - pharmacokinetics Medical sciences metabolism Pharmacology. Drug treatments Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacokinetics Receptors, Histamine H1 - chemistry Receptors, Histamine H1 - metabolism Structure-Activity Relationship structure-activity relationships
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.12.053