WorldWide Medicinal Chemistry: Inflammation & Immunology, Pfizer Global Research & Development, Cambridge, MA 01240, USA.
J Med Chem. 2010 Aug 26;53(16):6122-8. doi: 10.1021/jm100533p.
Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.
酸性哺乳动物几丁质酶 (AMCase) 是糖苷水解酶 18 家族 (EC 3.2.1.14) 的成员，它与哮喘等过敏性气道疾病的病理生理学有关。使用高通量筛选、片段筛选和虚拟筛选技术相结合的方法鉴定了 AMCase 的小分子抑制剂，并通过酶抑制和 NMR 和 Biacore 结合实验进行了表征。抑制剂与 AMCase 复合物的 X 射线结构表明，较大的、更有效的高内涵筛选 (HTS) 命中化合物，例如 5-(4-(2-(4-溴苯氧基)乙基)哌嗪-1-基)-1H-1,2,4-三唑-3-胺 1，从活性位点口袋延伸到一个疏水口袋。通过 FBS 鉴定的较小片段独立占据这两个口袋，并提出了连接片段的潜在策略。化合物 1 是一种 200 nM 的 AMCase 抑制剂，在口服给药后，可降低变应原攻击小鼠支气管肺泡灌洗液中的 AMCase 酶活性。
