N-Acyl pyrazoles: Effective and tunable inhibitors of serine hydrolases
| Autor: | Benjamin F. Cravatt, Shreyosree Chatterjee, Dale L. Boger, Srijana Ghimire, Katerina Otrubova |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Pyrazole 01 natural sciences Biochemistry Article Amidohydrolases Serine Structure-Activity Relationship chemistry.chemical_compound Fatty acid amide hydrolase Drug Discovery Hydrolase Animals Urea Enzyme Inhibitors Molecular Biology 010405 organic chemistry Organic Chemistry Serine hydrolase ABHD6 Monoacylglycerol Lipases Recombinant Proteins Rats 0104 chemical sciences Monoacylglycerol lipase 010404 medicinal & biomolecular chemistry chemistry Drug Design Pyrazoles Molecular Medicine lipids (amino acids peptides and proteins) Acyl group |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1693-1703 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2019.03.020 |
| Popis: | 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 Ki = 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect