title: 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.
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.
authors.affiliation: 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
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishichi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoh
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Miwatashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Imai
authors.forename: Reiko
authors.initials: R
authors.lastname: Saikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D018723:Bethanechol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*
chemical_list: D002800:Cholinesterase Inhibitors; D011758:Pyrroles; D015363:Quinolones; D018723:Bethanechol; C496138:8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one; D000110:Acetylcholinesterase