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.
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.
Ishichi
Yuji
Y
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
Sasaki
Mitsuru
M
Setoh
Masaki
M
Tsukamoto
Tetsuya
T
Miwatashi
Seiji
S
Nagabukuro
Hiroshi
H
Okanishi
Satoshi
S
Imai
Shigemitsu
S
Saikawa
Reiko
R
Doi
Takayuki
T
Ishihara
Yuji
Y
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*
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