Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (23), p.6269-6273
Main Authors: Gao, Zhongli, Hurst, William J, Czechtizky, Werngard, Hall, Daniel, Moindrot, Nicolas, Nagorny, Raisa, Pichat, Philippe, Stefany, David, Hendrix, James A, George, Pascal G
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacokinetics
Amides - pharmacology
Animals
Antidepressive Agents - chemistry
Antidepressive Agents - pharmacokinetics
Antidepressive Agents - pharmacology
CHO Cells
Cricetulus
Histamine Antagonists - chemistry
Histamine Antagonists - pharmacokinetics
Histamine Antagonists - pharmacology
Humans
Kinetics
Male
Mice
Pyrrolidines - chemistry
Pyrrolidines - pharmacokinetics
Pyrrolidines - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Histamine H3 - chemistry
Receptors, Histamine H3 - metabolism
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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.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2013.09.081