ADAMTS-5（软骨聚集蛋白聚糖酶-2）的N-((8-羟基-5-取代喹啉-7-基)(苯基)甲基)-2-苯氧基/氨基乙酰胺抑制剂
N-((8-hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2).
作者信息
Gilbert Adam M, Bursavich Matthew G, Lombardi Sabrina, Georgiadis Katy E, Reifenberg Erica, Flannery Carl R, Morris Elisabeth A
机构信息
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
出版信息
Bioorg Med Chem Lett. 2008 Dec 15;18(24):6454-7. doi: 10.1016/j.bmcl.2008.10.065. Epub 2008 Oct 18.
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
已制备出N-((8-羟基-5-取代喹啉-7-基)(苯基)甲基)-2-苯氧基/氨基乙酰胺类ADAMTS-5（软骨聚集蛋白聚糖酶-2）抑制剂。所选化合物10、14、25和53对ADAMTS-5具有亚微摩尔效力，并且对相关金属蛋白酶ADAMTS-4（软骨聚集蛋白聚糖酶-1）、MMP-13和MMP-12具有良好的选择性。化合物53在强效抑制ADAMTS-5、适度抑制CYP3A4和具有良好的大鼠肝微粒体稳定性之间展现出良好的平衡。这一系列化合物代表了在作为改善疾病的骨关节炎药物的选择性ADAMTS-5抑制剂方面取得的进展。
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