Discovery of Novel Steroid-Based Histamine H3 Receptor Antagonists/Inverse Agonists

Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the...

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Published inJournal of medicinal chemistry Vol. 67; no. 5; pp. 3643 - 3667
Main Authors Ledneczki, István, Tapolcsányi, Pál, Gábor, Eszter, Éles, János, Barabás, Júlia, Béni, Zoltán, Varga, Balázs, Balázs, Ottilia, Román, Viktor, Fodor, László, Szikra, Judit, Vastag, Mónika, Lévay, György, Schmidt, Éva, Lendvai, Balázs, Greiner, István, Kiss, Béla, Némethy, Zsolt, Mahó, Sándor
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.03.2024
Amer Chemical Soc
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ISSN0022-2623
1520-4804
1520-4804
DOI10.1021/acs.jmedchem.3c02117

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Summary:Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c02117