Butler Christopher R, Beck Elizabeth M, Harris Anthony, Huang Zhen, McAllister Laura A, Am Ende Christopher W, Fennell Kimberly, Foley Timothy L, Fonseca Kari, Hawrylik Steven J, Johnson Douglas S, Knafels John D, Mente Scot, Noell G Stephen, Pandit Jayvardhan, Phillips Tracy B, Piro Justin R, Rogers Bruce N, Samad Tarek A, Wang Jane, Wan Shuangyi, Brodney Michael A
Pfizer Worldwide Research and Development , 1 Portland Street, Cambridge, Massachusetts 02139, United States.
Pfizer Worldwide Research and Development , 445 Eastern Point Road, Groton, Connecticut 06340, United States.
J Med Chem. 2017 Dec 14;60(23):9860-9873. doi: 10.1021/acs.jmedchem.7b01531. Epub 2017 Dec 5.
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
单酰甘油脂肪酶（MAGL）是中枢神经系统中负责降解内源性大麻素2-花生四烯酸甘油酯（2-AG）的主要酶。MAGL催化2-AG转化为花生四烯酸（AA），花生四烯酸是促炎类二十烷酸（如前列腺素）的前体。在此，我们描述了通过平行药物化学方法鉴定出的高效MAGL抑制剂，该方法突出了氮杂环丁烷和哌啶衍生氨基甲酸酯的更高效率。MAGL的3-取代氮杂环丁烷氨基甲酸酯不可逆抑制剂的发现和优化得益于抑制剂结合的MAGL晶体结构的生成。化合物6是一种针对重组酶和在细胞环境中高效且选择性的MAGL抑制剂，已在体内进行测试，并显示在10 mg/kg剂量下可提高中枢2-AG水平。
