N-Acyl pyrazoles: Effective and tunable inhibitors of serine hydrolases. Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: Otrubova, Katerina; Chatterjee, Shreyosree; Ghimire, Srijana; Cravatt, Benjamin F.; Boger, Dale L.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 8(2019)
• Page Start: 1693
• Page End: 1703
• Publication Date: 2019-04-15
• Subjects: Serine hydrolase inhibitor -- N-acyl pyrazole -- Fatty acid amide hydrolase -- Monoacylglycerol hydrolase -- Activity-based protein profiling (ABPP); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.03.020
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of N -acyl pyrazoles was examined as candidate serine hydrolase inhibitors in which the active site acylating reactivity and the leaving group ability of the pyrazole could be tuned not only through the nature of the acyl group (reactivity: amide > carbamate > urea), but also through pyrazole C4 substitution with electron-withdrawing or electron-donating substituents. Their impact on enzyme inhibitory activity displayed pronounced effects with the activity improving substantially as one alters both the nature of the reacting carbonyl group (urea > carbamate > amide) and the pyrazole C4 substituent (CN > H > Me). It was further demonstrated that the acyl chain of the N -acyl pyrazole ureas can be used to tailor the potency and selectivity of the inhibitor class to a targeted serine hydrolase. Thus, elaboration of the acyl chain of pyrazole-based ureas provided remarkably potent, irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent K i = 100–200 pM), dual inhibitors of FAAH and monoacylglycerol hydrolase (MGLL), or selective inhibitors of MGLL (IC50 = 10–20 nM) while simultaneously minimizing off-target activity (e.g., ABHD6 and KIAA1363).