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. 2013 Dec 1;23(23):6269-73.
doi: 10.1016/j.bmcl.2013.09.081. Epub 2013 Oct 3.

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

Zhongli Gao  1 , William J Hurst, Werngard Czechtizky, Daniel Hall, Nicolas Moindrot, Raisa Nagorny, Philippe Pichat, David Stefany, James A Hendrix, Pascal G George
Affiliations

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

Zhongli Gao et al. Bioorg Med Chem Lett. .

Abstract

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.

Keywords: Anxiety; Depression; Experimental models of anxiety and depression; Forced swimming test; Histamine H(3) receptor antagonist/inverse agonist.

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