Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase
| Autor: | Maria João Bonifácio, Alexandre Beliaev, Humberto Ferreira, Carla Patricia da Costa Pereira Rosa, Patrício Soares-da-Silva, Nuno Pires, P. Nuno Palma, Ana I. Loureiro, Laszlo Erno Kiss |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male BIA 10-2474 Pyridines Administration Oral Pharmacology Biochemistry Amidohydrolases Cyclic N-Oxides 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Fatty acid amide hydrolase Drug Discovery Healthy volunteers fatty acid amide hydrolase Potency anandamide Animals Humans pain General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Analgesics Full Paper Clinical Trials Phase I as Topic Molecular Structure Chemistry Organic Chemistry Brain Anandamide Metabolic stability Full Papers Rats Monoacylglycerol lipase 030104 developmental biology Long acting Liver Drug Design target selectivity Microsomes Liver Molecular Medicine |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic‐N‐carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl‐ and imidazolyl‐N‐carboxamide series led to the discovery of clinical candidate 8 l (3‐(1‐(cyclohexyl(methyl)carbamoyl)‐1H‐imidazol‐4‐yl)pyridine 1‐oxide; BIA 10‐2474) as a potent and long‐acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject. |
| Databáze: | OpenAIRE |
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