Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.,ChemMedChem

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Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.
ChemMedChem ( IF 3.6 ) Pub Date : 2018-09-11 , DOI: 10.1002/cmdc.201800393
László E Kiss ₁ , Alexandre Beliaev ₁ , Humberto S Ferreira ₁ , Carla P Rosa ₁ , Maria João Bonifácio ₂ , Ana I Loureiro ₂ , Nuno M Pires ₂ , P Nuno Palma ₂ , Patrício Soares-da-Silva _{2,

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Affiliation

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.

中文翻译：

脂肪酸酰胺水解酶的有效，长效和CNS活性抑制剂（BIA 10-2474）的发现。

脂肪酸酰胺水解酶（FAAH）可以用于治疗与各种医学状况相关的疼痛。本文中，我们报告了一系列新颖的杂环N-羧酰胺FAAH抑制剂的设计和合成，这些抑制剂相对于单酰基甘油脂肪酶（MAGL）和羧酸酯酶（CEs）具有对FAAH的效力，代谢稳定性和选择性良好的一致性。使用苯并三唑基和咪唑基-N-羧酰胺系列进行的前导优化工作导致发现了临床候选药物8 l（3-（1-（环己基（甲基）氨基甲酰基）-1H-咪唑-4-基）吡啶1-氧化物; BIA 10-2474）作为FAAH的有效和长效抑制剂。但是，在使用化合物8 l进行的I期临床试验中，发生了意料不到且无法预测的严重神经系统不良事件，影响了五名健康志愿者，包括一名受试者的死亡。

更新日期：2018-09-11

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