Pfizer Global Research & Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA.
Bioorg Med Chem Lett. 2012 Jan 1;22(1):138-43. doi: 10.1016/j.bmcl.2011.11.046. Epub 2011 Nov 20.
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.
慢性阻塞性肺疾病（COPD）是一种与不可逆性进行性气流受限相关的肺部炎症性疾病。基质金属蛋白酶-12（MMP-12）已被确定为主要的蛋白水解酶之一，可诱导气道重塑、弹性蛋白破坏以及 COPD 和哮喘中受损肺泡的异常重塑。本项目的目标是开发和鉴定一种针对 MMP-12 的具有口服活性和选择性的小分子抑制剂，用于治疗 COPD 和哮喘。本文描述了一系列二苯并呋喃（DBF）磺酰胺作为 MMP-12 抑制剂的合成和构效关系（SAR）研究。已经鉴定出对 MMP-12 具有高抑制活性且对其他 MMP 具有极好选择性的抑制剂。化合物 26（MMP118）在 MMP-12 诱导的耳肿胀炎症和肺部炎症小鼠模型中具有优异的口服疗效，已成功进入开发阶段。
