title: 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 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.
authors.affiliation: Neurocrine Biosciences, San Diego, CA 92130, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Huang
authors.forename: Wilna J
authors.initials: WJ
authors.lastname: Moree
authors.forename: Said
authors.initials: S
authors.lastname: Zamani-Kord
authors.forename: Bin-Feng
authors.initials: BF
authors.lastname: Li
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Jianyun
authors.initials: J
authors.lastname: Wen
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Samuel R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Graham
authors.initials: G
authors.lastname: Beaton
mesh_terms: D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006634:Histamine H1 Antagonists; D007192:Indenes; D011719:Pyrazines; D011969:Receptors, Histamine H1; D019389:Cytochrome P-450 CYP2D6