Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 15, Pages 4392-4403Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm800136b
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Funding
- NIDA NIH HHS [DA15648, R01 DA015648-05, R01 DA015648] Funding Source: Medline
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The synthesis and evaluation of a refined series of (x-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity: 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatorn at position 4 (oxazole numbering, N > 0 > CH) substantially increases activity that may be attributed to a. reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
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