Discovery of a novel 5-HT(3) antagonist/5-HT(1A) agonist 3-amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878) as an orally bioavailable agent for irritable bowel syndrome
| Autor: | Hiroyuki Hayashi, Teruaki Matsui, Yukinao Yamauchi, Akira Asagarasu, Kouichi Minato, Michitaka Sato, Satoru Tamaoki |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
medicine.drug_class Stereochemistry Pyridines Guinea Pigs Administration Oral Biological Availability Pharmacology In Vitro Techniques Serotonin 5-HT1 Receptor Antagonists Piperazines Cell Line Irritable Bowel Syndrome chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Cricetulus In vivo Ileum 5-HT3 antagonist Cricetinae Drug Discovery Reflex medicine Animals Humans Serotonin 5-HT3 Receptor Antagonists Quinazolinone 5-HT receptor Quinazolinones Antagonist Brain Muscle Smooth Stereoisomerism Serotonin 5-HT1 Receptor Agonists Rats chemistry Receptor Serotonin 5-HT1A Quinolines Molecular Medicine Pharmacophore Receptors Serotonin 5-HT3 Linker medicine.drug Muscle Contraction |
| Zdroj: | Journal of medicinal chemistry. 53(21) |
| ISSN: | 1520-4804 2005-0828 |
| Popis: | We have prepared a series of quinazolinone derivatives linked with piperazinylquinoline for the treatment of irritable bowel syndrome (IBS). Using pharmacophore analysis, we designed and synthesized compounds which bind to both serotonin receptor subtype 1A (5-HT(1A)) and subtype 3 (5-HT(3)). Quinazolinone derivatives with a sulfur atom in the linker showed high affinity in in vitro assays, but low in vivo activity. Focusing on the linker to improve the pharmacokinetic profile, the sulfur atom in the linker was replaced with a methylene group. Further optimization led to the discovery of compound 17m (TZB-30878) ( J. Pharmacol. Exp. Ther. 2007 , 322 , 1315 - 1323 , Patent WO2005082887 (A1), 2005 ), a novel 5-HT(1A) agonist/5-HT(3) antagonist in the 3-aminoquinazolinone series. In in vivo functional assays, 17m dose dependently inhibited the Bezold-Jarisch reflex and induced 5-HT(1A)-mediated behaviors, and in an IBS animal model, 17m significantly inhibited stress-induced defecation. Pretreatment by WAY-100635 (5-HT(1A) antagonist) significantly attenuated but did not abolish the inhibitory effects of 17m. These results suggested that 17m exerted inhibitory effects via both 5-HT(1A) agonistic and 5-HT(3) antagonistic activities and that 17m would be useful as a therapeutic agent for IBS. |
| Databáze: | OpenAIRE |
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