Novel inhibitors of fatty acid amide hydrolase
Abstract
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
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- Authors
- Sit, S. Y., Conway, C., Bertekap, R., Xie, K., Bourin, C., Burris, K., & Deng, H.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- Palatin Technologies (United States) (US)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Sit, S.Y.
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 17
- Issue
- 12
- Pages
- 3287-3291
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2034008536
- Cited by
- 52
- References
- 29
- Citations by year
- 2024: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 1 · 2012: 2
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- fatty acid amide hydrolase, FAAH inhibitors, anandamide, antinociception, chronic pain, neuropathic pain, CB1 receptor, endocannabinoid system, gabapentin, morphine comparison
- MeSH terms
- Gabapentin, Rimonabant, Fatty Acid Amide Hydrolases, Amidohydrolases, Amines, Analgesics, Animals, Cyclohexanecarboxylic Acids, Dose-Response Relationship, Drug, Enzyme Inhibitors, gamma-Aminobutyric Acid, Humans, Imidazoles, Morphine, Pain Measurement, Piperidines, Pyrazoles, Mice, Knockout, Receptor, Cannabinoid, CB1, Mice, Rats
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