Literature DB >> 26713105

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279.

John M Keith1, William M Jones1, Mark Tichenor1, Jing Liu1, Mark Seierstad1, James A Palmer1, Michael Webb1, Mark Karbarz1, Brian P Scott1, Sandy J Wilson1, Lin Luo1, Michelle L Wennerholm1, Leon Chang1, Michele Rizzolio1, Raymond Rynberg1, Sandra R Chaplan1, J Guy Breitenbucher1.   

Abstract

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.

Entities:  

Keywords:  FAAH; anandamide; covalent; enzyme; ethanolamides

Year:  2015        PMID： 26713105      PMCID： PMC4677372          DOI： 10.1021/acsmedchemlett.5b00353

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  39 in total

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2.  An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.

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4.  Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.

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Journal:  Proc Natl Acad Sci U S A       Date:  2001-07-24       Impact factor: 11.205

Review 5.  Fatty acid amide signaling molecules.

Authors:  Cyrine Ezzili; Katerina Otrubova; Dale L Boger
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6.  Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor.

Authors:  Douglas S Johnson; Cory Stiff; Scott E Lazerwith; Suzanne R Kesten; Lorraine K Fay; Mark Morris; David Beidler; Marya B Liimatta; Sarah E Smith; David T Dudley; Nalini Sadagopan; Shobha N Bhattachar; Stephen J Kesten; Tyzoon K Nomanbhoy; Benjamin F Cravatt; Kay Ahn
Journal:  ACS Med Chem Lett       Date:  2011-02-10       Impact factor: 4.345

7.  Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.

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Review 8.  The palmitoylethanolamide family: a new class of anti-inflammatory agents?

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9.  Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors.

Authors:  Darin J Gustin; Zhihua Ma; Xiaoshan Min; Yihong Li; Christine Hedberg; Cris Guimaraes; Amy C Porter; Michelle Lindstrom; Dianna Lester-Zeiner; Guifen Xu; Timothy J Carlson; Shouhua Xiao; Cesar Meleza; Richard Connors; Zhulun Wang; Frank Kayser
Journal:  Bioorg Med Chem Lett       Date:  2011-02-17       Impact factor: 2.823

10.  1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase.

Authors:  John M Keith; Natalie Hawryluk; Richard L Apodaca; Allison Chambers; Joan M Pierce; Mark Seierstad; James A Palmer; Michael Webb; Mark J Karbarz; Brian P Scott; Sandy J Wilson; Lin Luo; Michelle L Wennerholm; Leon Chang; Michele Rizzolio; Sandra R Chaplan; J Guy Breitenbucher
Journal:  Bioorg Med Chem Lett       Date:  2014-01-31       Impact factor: 2.823
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Review 2.  Breaking barriers to novel analgesic drug development.

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Review 3.  On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence.

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Journal:  Neurotox Res       Date:  2021-11-06       Impact factor: 3.911

4.  Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

Authors:  Zhen Huang; Daisuke Ogasawara; Uthpala I Seneviratne; Armand B Cognetta; Christopher W Am Ende; Deane M Nason; Kimberly Lapham; John Litchfield; Douglas S Johnson; Benjamin F Cravatt
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5.  The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial.

Authors:  Martin P Paulus; Murray B Stein; Alan N Simmons; Victoria B Risbrough; Robin Halter; Sandra R Chaplan
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6.  Aryl N-[ω-(6-Fluoroindol-1-yl)alkyl]carbamates as Inhibitors of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and Butyrylcholinesterase: Structure-Activity Relationships and Hydrolytic Stability.

Authors:  Stefan Rudolph; Helmut Dahlhaus; Walburga Hanekamp; Christian Albers; Maximilian Barth; Giulia Michels; Denise Friedrich; Matthias Lehr
Journal:  ACS Omega       Date:  2021-05-14

7.  The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents.

Authors:  Guy Griebel; Jeanne Stemmelin; Mati Lopez-Grancha; Valérie Fauchey; Franck Slowinski; Philippe Pichat; Gihad Dargazanli; Ahmed Abouabdellah; Caroline Cohen; Olivier E Bergis
Journal:  Sci Rep       Date:  2018-02-05       Impact factor: 4.379

8.  Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation.

Authors:  Eric Murillo-Rodríguez; Vincenzo Di Marzo; Sergio Machado; Nuno B Rocha; André B Veras; Geraldo A M Neto; Henning Budde; Oscar Arias-Carrión; Gloria Arankowsky-Sandoval
Journal:  Front Mol Neurosci       Date:  2017-05-30       Impact factor: 5.639

9.  Fatty Acid Amide Hydrolase Inhibition by JNJ-42165279: A Multiple-Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers.

Authors:  Andrey Postnov; Mark E Schmidt; Darrel J Pemberton; Jan de Hoon; Anne van Hecken; Maarten van den Boer; Peter Zannikos; Peter van der Ark; James A Palmer; Stef Rassnick; Sofie Celen; Guy Bormans; Koen van Laere
Journal:  Clin Transl Sci       Date:  2018-03-25       Impact factor: 4.689

10.  Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.

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