Identification and characterization of acidic mammalian chitinase inhibitors.
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.
Cole
Derek C
DC
WorldWide Medicinal Chemistry: Inflammation & Immunology, Pfizer Global Research & Development, Cambridge, MA 01240, USA. derek.cole@takedasd.com
Olland
Andrea M
AM
Jacob
Jaison
J
Brooks
Jon
J
Bursavich
Matthew G
MG
Czerwinski
Robert
R
DeClercq
Charlene
C
Johnson
Mark
M
Joseph-McCarthy
Diane
D
Ellingboe
John W
JW
Lin
Laura
L
Nowak
Pawel
P
Presman
Ella
E
Strand
James
J
Tam
Amy
A
Williams
Cara M M
CM
Yao
Shihua
S
Tsao
Désirée H H
DH
Fitz
Lori J
LJ
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
D000485:Allergens; D010879:Piperazines; D014230:Triazoles; C499255:AMCase, mouse; D002688:Chitinases