Optimization of α-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase

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• 作者：F. Scott Kimball ; F. Anthony Romero ; Cyrine Ezzili ; Joie Garfunkle ; Thomas J. Rayl ; Dustin G. Hochstatter ; Inkyu Hwang ; Dale L. Boger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 28, 2008
• 年：2008
• 卷：51
• 期：4
• 页码：937 - 947
• 全文大小：307K
• 年卷期：v.51,no.4(February 28, 2008)
• ISSN：1520-4804

文摘

A series of α-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, K_i = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between −log K_i and Hammett σ_p of a magnitude (ρ = 2.7–3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.