Design,synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors |
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| Institution: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan;2. CMC Center, Takeda Pharmaceutical Company Ltd, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis 38163, USA;2. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA;3. Emory University School of Medicine, VA Medical Center, Medical Research 151H, 1670 Clairmont Road, Decatur, GA 30033, USA;4. UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States;1. Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India;2. Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India;1. Department of Chemistry, Wellesley College, Wellesley, MA 02481, USA;2. Department of Biological Sciences, Wellesley College, Wellesley, MA 02481, USA;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;1. Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Survey Nos: 125(part) & 126, IDA Mallapur, Hyderabad 500076, India;2. COEAMMPC & Division of Chemistry, Department of Sciences and Humanities, Vignan''s Foundation for Science, Technology and Research University (VFSTRU; Vignan University), Vadlamudi, Guntur 522 213, India;3. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India;4. Department of Biology, GVK Biosciences Pvt. Ltd., Survey Nos: 125(part) & 126, IDA Mallapur, Hyderabad 500076, India;5. Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India |
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| Abstract: | 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. |
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| Keywords: | Fatty acid amide hydrolase inhibitors Arachidonoylethanolamide Piperazine ureas Neuropathic pain Inflammatory pain |
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