Identification and Characterization of Acidic Mammalian Chitinase Inhibitors

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• 作者：Derek C. Cole ; Andrea M. Olland ; Jaison Jacob ; Jon Brooks ; Matthew G. Bursavich ; Robert Czerwinski ; Charlene DeClercq ; Mark Johnson ; Diane Joseph-McCarthy ; John W. Ellingboe ; Laura Lin ; Pawel Nowak ; E
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 26, 2010
• 年：2010
• 卷：53
• 期：16
• 页码：6122-6128
• 全文大小：963K
• 年卷期：v.53,no.16(August 26, 2010)
• ISSN：1520-4804

文摘

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.