Discovery of novel steroidal histamine H 3 receptor antagonists/inverse agonists

• Published in: Bioorganic & 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
• Language: English
• Published: OXFORD Elsevier 01.10.2017
• Subjects: Animals; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Histamine Agonists - chemical synthesis; Histamine Agonists - chemistry; Histamine Agonists - pharmacology; Histamine H3 Antagonists - chemical synthesis; Histamine H3 Antagonists - chemistry; Histamine H3 Antagonists - pharmacology; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Rats; Receptors, Histamine H3 - metabolism; Science & Technology; Structure-Activity Relationship; Steroid; NERVOUS-SYSTEM; ACTIVATION; ACETYLCHOLINE; DISORDERS; RELEASE; Estrane derivatives; Antagonist/inverse agonist; INHIBITION; THERAPEUTIC TARGET; Histamine H-3 receptor; H-3-RECEPTOR; Dipsogenia model; RAT-BRAIN CORTEX; CONESSINE; Histamine H receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.08.060

Emerging from an HTS campaign, novel steroid-based histamine H-3 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 H-3 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. (C) 2017 Elsevier Ltd. All rights reserved.