Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds

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• 作者：Hans Hilpert ; Harald Mauser ; Roland Humm ; Lilli Anselm ; Holger Kuehne ; Guido Hartmann ; Sabine Gruener ; David W. Banner ; Joerg Benz ; Bernard Gsell ; Andreas Kuglstatter ; Martine Stihle ; Ralf Thoma ; Rub茅n Alvarez Sanchez ; Hans Iding ; Beat Wirz ; Wolfgang Haap
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9789-9801
• 全文大小：574K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50鈥?00-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand鈥搑eceptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED₅₀ of 5 mg/kg.