Novel acetylcholinesterase inhibitor as increasing agent on rhythmic bladder contractions: SAR of 8-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (TAK-802) and related compounds

Yuji Ishichi; Mitsuru Sasaki; Masaki Setoh; Tetsuya Tsukamoto; Seiji Miwatashi; Hiroshi Nagabukuro; Satoshi Okanishi; Shigemitsu Imai; Reiko Saikawa; Takayuki Doi; Yuji Ishihara

doi:10.1016/j.bmc.2005.01.022

Novel acetylcholinesterase inhibitor as increasing agent on rhythmic bladder contractions: SAR of 8-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (TAK-802) and related compounds

Bioorg Med Chem. 2005 Mar 15;13(6):1901-11. doi: 10.1016/j.bmc.2005.01.022.

Authors

Yuji Ishichi¹, Mitsuru Sasaki, Masaki Setoh, Tetsuya Tsukamoto, Seiji Miwatashi, Hiroshi Nagabukuro, Satoshi Okanishi, Shigemitsu Imai, Reiko Saikawa, Takayuki Doi, Yuji Ishihara

Affiliation

¹ Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Ishihara_Yuji@takeda.co.jp

PMID: 15727846
DOI: 10.1016/j.bmc.2005.01.022

Abstract

As part of an on-going investigation to develop an increasing agent on rhythmic bladder contractions, 1-aryl-3-(1-benzylpiperidin-4-yl)propanones were synthesized and examined as noncarbamate acetylcholinesterase (AChE) inhibitors. Among compounds with various aryl groups, 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one derivative 9c was found to possess a potent AChE inhibition activity with an IC(50) value of 1.3nM. The compound 9c increased rhythmic bladder contractions in Guinea pigs and rats without affecting the basal intravesical pressure, which suggests that 9c may be useful for the treatment of voiding dysfunction caused by detrusor underactivity.

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Bethanechol / chemical synthesis
Bethanechol / chemistry
Bethanechol / pharmacology
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Guinea Pigs
Inhibitory Concentration 50
Male
Molecular Structure
Muscle Contraction / drug effects
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology*
Quinolones / chemical synthesis
Quinolones / chemistry*
Quinolones / pharmacology*
Rats
Structure-Activity Relationship
Urinary Bladder / drug effects*
Urinary Bladder / enzymology
Urinary Bladder / physiology*

Substances

Cholinesterase Inhibitors
Pyrroles
Quinolones
Bethanechol
8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one
Acetylcholinesterase