Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3a2S)-2-methyl-[1,3a2]bipyrrolidinyl-1a2-yl)phe nyl] amide as histamine H3 receptor antagonist for the treatment of depression

Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonis...

Full description

Saved in:
Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 23; no. 23; pp. 6269 - 6273
Main Authors Gao, Zhongli, Hurst, William, Czechtizky, Werngard, Hall, Daniel, Moindrot, Nicolas, Nagorny, Raisa, Pichat, Philippe, Stefany, David, Hendrix, James, George, Pascal
Format Journal Article
LanguageEnglish
Published 01.12.2013
Subjects
Central nervous system
Online AccessGet full text

Cover

More Information
Summary:Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
content type line 23
ObjectType-Feature-1
ISSN:0960-894X
DOI:10.1016/j.bmcl.2013.09.081