ArticleJournal of medicinal chemistry2011
Reversible competitive α-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 49 citations in OpenAlex.
- In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors.Molecules (Basel, Switzerland) · 2020Article
- N-Acyl pyrazoles: Effective and tunable inhibitors of serine hydrolases.Bioorganic & medicinal chemistry · 2019Article
- Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.ChemMedChem · 2018Article
- The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface.The Journal of organic chemistry · 2017Article
- Comprehensive Analysis of Structure-Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors.Journal of medicinal chemistry · 2015Article
- Discovery libraries targeting the major enzyme classes: the serine hydrolases.Bioorganic & medicinal chemistry letters · 2014Article
- α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain.Bioorganic & medicinal chemistry · 2014Article
- Design, synthesis, and characterization of α-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase.Journal of medicinal chemistry · 2014Article
- Rational design of fatty acid amide hydrolase inhibitors that act by covalently bonding to two active site residues.Journal of the American Chemical Society · 2013Article
- Chemical probes of endocannabinoid metabolism.Pharmacological reviews · 2013Review
- A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase.Journal of the American Chemical Society · 2013Article
- Potent inhibition of norovirus 3CL protease by peptidyl α-ketoamides and α-ketoheterocycles.Bioorganic & medicinal chemistry letters · 2012Article
- α-Ketoheterocycle-based Inhibitors of Fatty Acid Amide Hydrolase (FAAH).ACS chemical neuroscience · 2012Article
- Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice.Pharmacology, biochemistry, and behavior · 2011Article
- The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH).Bioorganic & medicinal chemistry letters · 2011Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
A series of α-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the α-ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (ip) or oral (po) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5 and 3 h, and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (>6 h) and cold (>9 h) allodynia for sustained periods consistent with its long-acting effects in raising the endogenous concentration of anandamide.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.