Matrix Metalloproteinase Inhibitors Based on the 3-Mercaptopyrrolidine Core

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• 作者：Yonghao Jin ; Mark D. Roycik ; Dale B. Bosco ; Qiang Cao ; Manuel H. Constantino ; Martin A. Schwartz ; Qing-Xiang Amy Sang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4357-4373
• 全文大小：616K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (2 to 50 nM), MMP-13 (2 to 50 nM), and MMP-14 (4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, 850 to >50鈥?00 nM; MMP-7, 4000 to >25鈥?00 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.