ArticleJournal of the American Chemical Society2013
Rational design of fatty acid amide hydrolase inhibitors that act by covalently bonding to two active site residues.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.Frontiers in neuroscience · 2023Article
- Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition.International journal of molecular sciences · 2022Article
- Efficacy coefficient method assisted quadruple-activities 3D-QSAR pharmacophore model for application in environmentally friendly PAE molecular modification.Environmental science and pollution research international · 2020Article
- An endocannabinoid catabolic enzyme FAAH and its paralogs in an early land plant reveal evolutionary and functional relationship with eukaryotic orthologs.Scientific reports · 2020Article
- Arylfluorosulfate-Based Electrophiles for Covalent Protein Labeling: A New Addition to the Arsenal.Angewandte Chemie (International ed. in English) · 2019Review
- Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.ChemMedChem · 2018Article
- PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors.Journal of the American Chemical Society · 2017Article
- The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface.The Journal of organic chemistry · 2017Article
- Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse.Neuropharmacology · 2017Article
- TBHP-mediated highly efficient dehydrogenative cross-oxidative coupling of methylarenes with acetanilides.Beilstein journal of organic chemistry · 2016Article
- Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets.PLoS computational biology · 2015Article
- O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors.ChemMedChem · 2015Article
- Article
- 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
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The design and characterization of α-ketoheterocycle fatty acid amide hydrolase (FAAH) inhibitors are disclosed that additionally and irreversibly target a cysteine (Cys269) found in the enzyme cytosolic port while maintaining the reversible covalent Ser241 attachment responsible for their rapid and initially reversible enzyme inhibition. Two α-ketooxazoles (3 and 4) containing strategically placed electrophiles at the C5 position of the pyridyl substituent of 2 (OL-135) were prepared and examined as inhibitors of FAAH. Consistent with the observed time-dependent noncompetitive inhibition, the cocrystal X-ray structure of 3 bound to a humanized variant of rat FAAH revealed that 3 was not only covalently bound to the active site catalytic nucleophile Ser241 as a deprotonated hemiketal, but also to Cys269 through the pyridyl C5-substituent, thus providing an inhibitor with dual covalent attachment in the enzyme active site. In vivo characterization of the prototypical inhibitors in mice demonstrates that they raise endogenous brain levels of FAAH substrates to a greater extent and for a much longer duration (>6 h) than the reversible inhibitor 2, indicating that the inhibitors accumulate and persist in the brain to completely inhibit FAAH for a prolonged period. Consistent with this behavior and the targeted irreversible enzyme inhibition, 3 reversed cold allodynia in the chronic constriction injury model of neuropathic pain in mice for a sustained period (>6 h) beyond that observed with the reversible inhibitor 2, providing effects that were unchanged over the 1-6 h time course monitored.
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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.