Design, synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors.
A series of piperazine ureas were designed, synthesized, and evaluated for their potential as novel orally efficacious fatty acid amide hydrolase (FAAH) inhibitors for the treatment of neuropathic and inflammatory pain. We carried out an optimization study of compound 5 to improve its in vitro FAAH inhibitory activity, and identified the 2-pyrimidinylpiperazine derivative 21d with potent inhibitory activity, favorable DMPK profile and brain permeability. Compound 21d showed robust and dose-dependent analgesic efficacy in animal models of both neuropathic and inflammatory pain.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: mitsunori.kouno@takeda.com.
Mitsunori
M
Kono
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Takahiro
T
Matsumoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Toshihiro
T
Imaeda
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Toru
T
Kawamura
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Shinji
S
Fujimoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Yohei
Y
Kosugi
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Tomoyuki
T
Odani
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Yuji
Y
Shimizu
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Hideki
H
Matsui
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masato
M
Shimojo
CMC Center, Takeda Pharmaceutical Company Ltd, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan.
Masakuni
M
Kori
D000284:Administration, Oral; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000188:drug therapy; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D004791:Enzyme Inhibitors; D000077489:Piperazine; D010879:Piperazines; D011724:Pyridazines; D011743:Pyrimidines; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C000591914:4-(4-(3,4-difluorophenyl)pyrimidin-2-yl)-N-(pyridazin-3-yl)piperazine-1-carboxamide
Arachidonoylethanolamide; Fatty acid amide hydrolase inhibitors; Inflammatory pain; Neuropathic pain; Piperazine ureas