Li Wei, Li Jianchang, Wu Yuchuan, Rancati Fabio, Vallese Stefania, Raveglia Luca, Wu Junjun, Hotchandani Rajeev, Fuller Nathan, Cunningham Kristina, Morgan Paul, Fish Susan, Krykbaev Rustem, Xu Xin, Tam Steve, Goldman Samuel J, Abraham William, Williams Cara, Sypek Joseph, Mansour Tarek S
Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA.
J Med Chem. 2009 Sep 10;52(17):5408-19. doi: 10.1021/jm900809r.
MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.
基质金属蛋白酶-12（MMP-12）在气道炎症和重塑过程中发挥着重要作用。在哮喘患者的肺部已观察到MMP-12的表达和产生增加。化合物27被鉴定为一种具有良好理化性质的强效且选择性的MMP-12抑制剂。在药理学研究中，该化合物在MMP-12诱导的小鼠耳部肿胀炎症模型中口服有效，具有良好的剂量反应。该化合物在自然感染蛔虫致敏的绵羊哮喘模型中也表现出口服有效性，对过敏原激发的迟发反应有显著抑制作用。该化合物已被考虑进一步开发作为哮喘的治疗药物。
