- Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase
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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.
- Kiss, László E.,Beliaev, Alexandre,Ferreira, Humberto S.,Rosa, Carla P.,Bonifácio, Maria Jo?o,Loureiro, Ana I.,Pires, Nuno M.,Palma, P. Nuno,Soares-da-Silva, Patrício
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p. 2177 - 2188
(2018/09/25)
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- PROCESS FOR THE SYNTHESIS OF SUBSTITUTED UREA COMPOUNDS
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A process for preparing a substituted urea compound of Formula II or Formula I, or a pharmaceutically acceptable salt or ester thereof, Formula II, Formula I the process comprising the reaction of an intermediate of Formula II' or Formula 1', Formula II',
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- PHARMACEUTICAL COMPOUNDS
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The invention relates to compounds and compositions for inhibiting the enzyme fatty acid amide hydrolase (FAAH), the use of the compounds in therapy and, in particular, for treating or preventing conditions whose development or symptoms are linked to subs
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- PROCESS FOR THE SYNTHESIS OF SUBSTITUTED UREA COMPOUNDS
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A process for preparing a substitute urea of Formula (II) or Formula (I), or a pharmaceutically acceptable salt or ester thereof, Formula (II): Formula (I): the process comprising the reaction of a carbamate of Formula (II'): or formula (I'): with a prima
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