Discovery of novel steroidal histamine H 3 receptor antagonists/inverse agonists
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 versati...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 27; no. 19; pp. 4525 - 4530 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
OXFORD
Elsevier
01.10.2017
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| Online Access | Get full text |
| ISSN | 0960-894X 1464-3405 |
| DOI | 10.1016/j.bmcl.2017.08.060 |
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| Abstract | 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. |
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| AbstractList | 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. Emerging from an HTS campaign, novel steroid-based histamine H 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 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. |
| Author | Tapolcsányi, Pál Schmidt, Éva Balázs, Ottilia Némethy, Zsolt Greiner, István Román, Viktor Kedves, Rita Soukupné Gábor, Eszter Éles, János Ledneczki, Istvan Lévay, György Mahó, Sándor |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28888822$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1016_j_bmcl_2019_126643 crossref_primary_10_3390_ph12020099 crossref_primary_10_1016_j_bmc_2022_116882 crossref_primary_10_1021_acs_jmedchem_3c02117 crossref_primary_10_1080_13543776_2018_1424135 crossref_primary_10_1021_acscatal_0c02030 |
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| Keywords | 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 |
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| SubjectTerms | 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 |
| Title | Discovery of novel steroidal histamine H 3 receptor antagonists/inverse agonists |
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