title: Optimization of the central heterocycle of alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase.
abstract: The synthesis and evaluation of a refined series of alpha-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 heteroatom at position 4 (oxazole numbering, N > O > 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.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA.
authors.forename: Joie
authors.initials: J
authors.lastname: Garfunkle
authors.forename: Cyrine
authors.initials: C
authors.lastname: Ezzili
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rayl
authors.forename: Dustin G
authors.initials: DG
authors.lastname: Hochstatter
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004583:Electrons; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D008745:Methylation; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001393:Azoles; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010080:Oxazoles; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases