Novel benzothiophene H1-antihistamines for the treatment of insomnia.
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
Moree
Wilna J
WJ
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. wilna.moree@gmail.com
Jovic
Florence
F
Coon
Timothy
T
Yu
Jinghua
J
Li
Bin-Feng
BF
Tucci
Fabio C
FC
Marinkovic
Dragan
D
Gross
Raymond S
RS
Malany
Siobhan
S
Bradbury
Margaret J
MJ
Hernandez
Lisa M
LM
O'Brien
Zhihong
Z
Wen
Jianyun
J
Wang
Hua
H
Hoare
Samuel R J
SR
Petroski
Robert E
RE
Sacaan
Aida
A
Madan
Ajay
A
Crowe
Paul D
PD
Beaton
Graham
G
D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D011969:Receptors, Histamine H1 / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D013876:Thiophenes; C088015:benzothiophene