2 research outputs found
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 <b>7f</b> as
a highly potent AMCase inhibitor (IC<sub>50</sub> 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 <b>7f</b> in the clinically relevant aeroallergen-induced
acute asthma model in mice provides a rationale for developing AMCase
inhibitor for the treatment of asthma
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 <b>7f</b> as
a highly potent AMCase inhibitor (IC<sub>50</sub> 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 <b>7f</b> in the clinically relevant aeroallergen-induced
acute asthma model in mice provides a rationale for developing AMCase
inhibitor for the treatment of asthma