1. Academic Validation
  2. Discovery of Novel Steroid-Based Histamine H3 Receptor Antagonists/Inverse Agonists

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

  • J Med Chem. 2024 Feb 23. doi: 10.1021/acs.jmedchem.3c02117.
István Ledneczki 1 Pál Tapolcsányi 1 Eszter Gábor 1 János Éles 1 Júlia Barabás 1 Zoltán Béni 1 Balázs Varga 1 Ottilia Balázs 1 Viktor Román 1 László Fodor 1 Judit Szikra 1 Mónika Vastag 1 György Lévay 1 Éva Schmidt 1 Balázs Lendvai 1 István Greiner 1 Béla Kiss 1 Zsolt Némethy 1 Sándor Mahó 1
Affiliations

Affiliation

  • 1 Gedeon Richter Plc., 19-21 Gyömrői út, Budapest H-1103, Hungary.
Abstract

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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