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Herein we report the design and synthesis of a novel series of heterocyclic\u2010<jats:italic>N<\/jats:italic>\u2010carboxamide 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\u2010 and imidazolyl\u2010<jats:italic>N<\/jats:italic>\u2010carboxamide series led to the discovery of clinical candidate <jats:bold>8\u2009l<\/jats:bold> (3\u2010(1\u2010(cyclohexyl(methyl)carbamoyl)\u20101<jats:italic>H<\/jats:italic>\u2010imidazol\u20104\u2010yl)pyridine 1\u2010oxide; BIA 10\u20102474) as a potent and long\u2010acting inhibitor of FAAH. However, during a Phase\u2005I clinical trial with compound <jats:bold>8\u2009l<\/jats:bold>, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.<\/jats:p>","DOI":"10.1002\/cmdc.201800393","type":"journal-article","created":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T07:47:00Z","timestamp":1534405620000},"page":"2177-2188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Discovery of a Potent, Long\u2010Acting, and CNS\u2010Active Inhibitor (BIA 10\u20102474) of Fatty Acid Amide Hydrolase"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1306-8752","authenticated-orcid":false,"given":"L\u00e1szl\u00f3 E.","family":"Kiss","sequence":"first","affiliation":[{"name":"Laboratory of Chemistry, Department of Research and Development BIAL-Portela &amp; C\u00aa., S.A.  \u00c0 Avenida da Siderurgia Nacional 4745-457 Coronado (S. 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