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

Akira Asagarasu; Teruaki Matsui; Hiroyuki Hayashi; Satoru Tamaoki; Yukinao Yamauchi; Kouichi Minato; Michitaka Sato

doi:10.1021/jm1002292

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

J Med Chem. 2010 Nov 11;53(21):7549-63. doi: 10.1021/jm1002292.

Authors

Akira Asagarasu¹, Teruaki Matsui, Hiroyuki Hayashi, Satoru Tamaoki, Yukinao Yamauchi, Kouichi Minato, Michitaka Sato

Affiliation

¹ Synthetic Research Department, ASKA Pharmaceutical Co, Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. asagarasu-a@aska-pharma.co.jp

PMID: 20931963
DOI: 10.1021/jm1002292

Abstract

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.

MeSH terms

Administration, Oral
Animals
Biological Availability
Brain / metabolism
Cell Line
Cricetinae
Cricetulus
Guinea Pigs
Humans
Ileum / drug effects
Ileum / physiology
In Vitro Techniques
Irritable Bowel Syndrome / drug therapy*
Irritable Bowel Syndrome / physiopathology
Muscle Contraction / drug effects
Muscle, Smooth / drug effects
Muscle, Smooth / physiology
Piperazines / pharmacology
Pyridines / pharmacology
Quinazolinones / chemical synthesis*
Quinazolinones / chemistry
Quinazolinones / pharmacology
Quinolines / chemical synthesis*
Quinolines / chemistry
Quinolines / pharmacology
Radioligand Assay
Rats
Receptor, Serotonin, 5-HT1A / metabolism
Receptors, Serotonin, 5-HT3 / metabolism
Reflex / drug effects
Serotonin 5-HT1 Receptor Agonists / chemical synthesis*
Serotonin 5-HT1 Receptor Agonists / chemistry
Serotonin 5-HT1 Receptor Agonists / pharmacology
Serotonin 5-HT1 Receptor Antagonists / pharmacology
Serotonin 5-HT3 Receptor Antagonists / chemical synthesis*
Serotonin 5-HT3 Receptor Antagonists / chemistry
Serotonin 5-HT3 Receptor Antagonists / pharmacology
Stereoisomerism
Structure-Activity Relationship

Substances

3-amino-5,6,7,8-tetrahydro-2-(4-(4-(quinolin-2-yl)piperazin-1-yl)butyl)quinazolin-4-(3H)-one
Piperazines
Pyridines
Quinazolinones
Quinolines
Receptors, Serotonin, 5-HT3
Serotonin 5-HT1 Receptor Agonists
Serotonin 5-HT1 Receptor Antagonists
Serotonin 5-HT3 Receptor Antagonists
Receptor, Serotonin, 5-HT1A
N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide