Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
Moree
Wilna J
WJ
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com
Li
Bin-Feng
BF
Zamani-Kord
Said
S
Yu
Jinghua
J
Coon
Timothy
T
Huang
Charles
C
Marinkovic
Dragan
D
Tucci
Fabio C
FC
Malany
Siobhan
S
Bradbury
Margaret J
MJ
Hernandez
Lisa M
LM
Wen
Jianyun
J
Wang
Hua
H
Hoare
Samuel R J
SR
Petroski
Robert E
RE
Jalali
Kayvon
K
Yang
Chun
C
Sacaan
Aida
A
Madan
Ajay
A
Crowe
Paul D
PD
Beaton
Graham
G
D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004115:Dimethindene / Q000737:chemistry; D004569:Electroencephalography; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007192:Indenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D006634:Histamine H1 Antagonists; D007192:Indenes; D011724:Pyridazines; D011969:Receptors, Histamine H1; D004115:Dimethindene; C093581:indene; D019389:Cytochrome P-450 CYP2D6