3 years ago

Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

Targeting Acidic
Mammalian chitinase Is Effective in Animal Model of Asthma
Paul Beckett, Agnieszka Zagozdzon, Sylwia Olejniczak, Karolina Dzwonek, Wojciech Czestkowski, Tom Noonan, William M. Hungerford, Robert Koralewski, Marzena Mazur, Firas Fadel, Keyvan Mahboubi, Alexandra Cousido-Siah, Barbara Dymek, Jakub Golab, Adam Golebiowski, Ryan Sheeler, Bruce Conway, Andre Mitschler, Piotr L. Sklepkiewicz, Alberto Podjarny, Jacek Olczak, Anna Jedrzejczak
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01051

DOI: 10.1021/acs.jmedchem.7b01051

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