title: Identification and characterization of acidic mammalian chitinase inhibitors.
abstract: 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.
authors.affiliation: WorldWide Medicinal Chemistry: Inflammation & Immunology, Pfizer Global Research & Development, Cambridge, MA 01240, USA. derek.cole@takedasd.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Olland
authors.forename: Jaison
authors.initials: J
authors.lastname: Jacob
authors.forename: Jon
authors.initials: J
authors.lastname: Brooks
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Robert
authors.initials: R
authors.lastname: Czerwinski
authors.forename: Charlene
authors.initials: C
authors.lastname: DeClercq
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Laura
authors.initials: L
authors.lastname: Lin
authors.forename: Pawel
authors.initials: P
authors.lastname: Nowak
authors.forename: Ella
authors.initials: E
authors.lastname: Presman
authors.forename: James
authors.initials: J
authors.lastname: Strand
authors.forename: Amy
authors.initials: A
authors.lastname: Tam
authors.forename: Cara M M
authors.initials: CM
authors.lastname: Williams
authors.forename: Shihua
authors.initials: S
authors.lastname: Yao
authors.forename: Désirée H H
authors.initials: DH
authors.lastname: Tsao
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Fitz
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D020134:Catalytic Domain; D002688:Chitinases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000485:Allergens; D010879:Piperazines; D014230:Triazoles; C499255:AMCase, mouse; D002688:Chitinases