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Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01051 Marzena Mazur 1 , Jacek Olczak 1 , Sylwia Olejniczak 1 , Robert Koralewski 1 , Wojciech Czestkowski 1 , Anna Jedrzejczak 1 , Jakub Golab 1, 2 , Karolina Dzwonek 1 , Barbara Dymek 1 , Piotr L. Sklepkiewicz 1 , Agnieszka Zagozdzon 1 , Tom Noonan 1 , Keyvan Mahboubi 1 , Bruce Conway 1 , Ryan Sheeler 1 , Paul Beckett 3 , William M. Hungerford 3 , Alberto Podjarny 4 , Andre Mitschler 4 , Alexandra Cousido-Siah 4 , Firas Fadel 4 , Adam Golebiowski 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01051 Marzena Mazur 1 , Jacek Olczak 1 , Sylwia Olejniczak 1 , Robert Koralewski 1 , Wojciech Czestkowski 1 , Anna Jedrzejczak 1 , Jakub Golab 1, 2 , Karolina Dzwonek 1 , Barbara Dymek 1 , Piotr L. Sklepkiewicz 1 , Agnieszka Zagozdzon 1 , Tom Noonan 1 , Keyvan Mahboubi 1 , Bruce Conway 1 , Ryan Sheeler 1 , Paul Beckett 3 , William M. Hungerford 3 , Alberto Podjarny 4 , Andre Mitschler 4 , Alexandra Cousido-Siah 4 , Firas Fadel 4 , Adam Golebiowski 1
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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.
中文翻译：
靶向酸性哺乳动物几丁质酶在哮喘动物模型中有效
本文重点介绍了我们在鉴定有效，选择性和有效的酸性哺乳动物几丁质酶（AMCase）抑制剂方面的工作。通过对与人壳三糖苷酶（hCHIT1）结合的几种抑制剂进行X射线分析指导的合理设计，导致化合物7f被鉴定为高效AMCase抑制剂（针对人和小鼠酶的IC 50值分别为14和19 nM）选择性（对mCHIT1大于150倍），具有非常好的PK特性。每天一次以30 mg / kg po给药的这种化合物在HDM诱导的小鼠过敏性气道炎症中显示出显着的抗炎功效，减少了BALF中炎性细胞的流入以及血浆中的总IgE浓度，这与甲壳质分解活性的降低有关。复方的治疗功效临床上相关的由气致敏原诱发的小鼠急性哮喘模型中的7f为开发用于治疗哮喘的AMCase抑制剂提供了理论依据。
更新日期：2018-01-11
中文翻译：
靶向酸性哺乳动物几丁质酶在哮喘动物模型中有效
本文重点介绍了我们在鉴定有效，选择性和有效的酸性哺乳动物几丁质酶（AMCase）抑制剂方面的工作。通过对与人壳三糖苷酶（hCHIT1）结合的几种抑制剂进行X射线分析指导的合理设计，导致化合物7f被鉴定为高效AMCase抑制剂（针对人和小鼠酶的IC 50值分别为14和19 nM）选择性（对mCHIT1大于150倍），具有非常好的PK特性。每天一次以30 mg / kg po给药的这种化合物在HDM诱导的小鼠过敏性气道炎症中显示出显着的抗炎功效，减少了BALF中炎性细胞的流入以及血浆中的总IgE浓度，这与甲壳质分解活性的降低有关。复方的治疗功效临床上相关的由气致敏原诱发的小鼠急性哮喘模型中的7f为开发用于治疗哮喘的AMCase抑制剂提供了理论依据。
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