3OJ8

Alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain

Summary for 3OJ8

• Entry DOI: 10.2210/pdb3oj8/pdb
• Related: 2vya 2wap 2wj1 2wj2 3k7f 3lj6
• Descriptor: Fatty-acid amide hydrolase 1, (S)-[(2S)-6-phenoxy-1,2,3,4-tetrahydronaphthalen-2-yl](5-pyridin-2-yl-1,3-oxazol-2-yl)methanol, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: protein-inhibitor complex, faah, oxazole, enantiomer, serine hydrolase, membrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Endoplasmic reticulum membrane; Single-pass membrane protein: P97612
• Total number of polymer chains: 2
• Total formula weight: 127055.69

Authors

Mileni, M.,Stevens, R.C.,Boger, D.L. (deposition date: 2010-08-20, release date: 2011-07-06, Last modification date: 2024-11-20)

Primary citation

Ezzili, C.,Mileni, M.,McGlinchey, N.,Long, J.Z.,Kinsey, S.G.,Hochstatter, D.G.,Stevens, R.C.,Lichtman, A.H.,Cravatt, B.F.,Bilsky, E.J.,Boger, D.L.
alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain
J.Med.Chem., 54:2805-2822, 2011

PubMed 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.

PubMed: 21428410
DOI: 10.1021/jm101597x

Experimental method

X-RAY DIFFRACTION (1.9 Å)