Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists

[Display omitted] Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization d...

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Published inBioorganic & medicinal chemistry letters Vol. 27; no. 19; pp. 4525 - 4530
Main Authors Ledneczki, Istvan, Tapolcsányi, Pál, Gábor, Eszter, Éles, János, Greiner, István, Schmidt, Éva, Némethy, Zsolt, Kedves, Rita Soukupné, Balázs, Ottilia, Román, Viktor, Lévay, György, Mahó, Sándor
Format Journal Article
LanguageEnglish
Published Elsevier Ltd 01.10.2017
Subjects
Antagonist/inverse agonist
Dipsogenia model
Estrane derivatives
Histamine H3 receptor
Steroid
Steroid
Antagonist/inverse agonist
Histamine H3 receptor
Estrane derivatives
Dipsogenia model
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ISSN0960-894X
1464-3405
1464-3405
DOI10.1016/j.bmcl.2017.08.060

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Summary:[Display omitted] Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.
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ISSN:0960-894X
1464-3405
1464-3405
DOI:10.1016/j.bmcl.2017.08.060