Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

This article highlights our work
toward the identification of a potent, selective, and efficacious
acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided
by X-ray analysis of several inhibitors bound to human chitotriosidase
(hCHIT1), led to the identification of compound 7f as
a highly potent AMCase inhibitor (IC50 values of 14 and
19 nM against human and mouse enzyme, respectively) and selective
(>150× against mCHIT1) with very good PK properties. This
compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory
efficacy in HDM-induced allergic airway inflammation in mice, reducing
inflammatory cell influx in the BALF and total IgE concentration in
plasma, which correlated with decrease of chitinolytic activity. Therapeutic
efficacy of compound 7f in the clinically relevant aeroallergen-induced
acute asthma model in mice provides a rationale for developing AMCase
inhibitor for the treatment of asthma.