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J Med Chem. 2010 Aug 26;53(16):6122-8. doi: 10.1021/jm100533p.

Identification and characterization of acidic mammalian chitinase inhibitors.

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WorldWide Medicinal Chemistry: Inflammation & Immunology, Pfizer Global Research & Development, Cambridge, MA 01240, USA.


Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 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.

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