Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase.

Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Research Abstract Details 

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Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Abstract Text:

Christophe Hardouin,Michael J Kelso,F Anthony Romero,Thomas J Rayl,Donmienne Leung,Inkyu Hwang,Benjamin F Cravatt,Dale L Boger,

A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM), with 5hh (aryl = 3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.

Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Publishing Authors By Initials

C Hardouin,MJ Kelso,FA Romero,TJ Rayl,D Leung,I Hwang,BF Cravatt,DL Boger,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of medicinal chemistry

VOLUME: 50

Page Numbers: 3359-68

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 9

MONTH: 06

YEAR: 2007

Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9716531

Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase. Information

Substance Name: fatty-acid amide hydrolase

Registry Number: EC 3.5.1.-

Grant and Affiliation Information for Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase.

AFFILIATION: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Country: United States

AGENCY: United States NIDA

GRANT: DA15648

ACRONYM: DA

MEDLINETA: J Med Chem

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