Design and Synthesis of a Series of (2R)-N 4-Hydroxy-2-(3-hydroxybenzyl)-N - [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl]butanediamide Derivatives as Potent, Selective, and Orally Bioavailable Aggrecanase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 44; no. 21; pp. 3347 - 3350
• Main Authors: Yao, Wenqing, Wasserman, Zelda R, Chao, Michael, Reddy, Gade, Shi, Eric, Liu, Rui-Qin, Covington, Maryanne B, Arner, Elizabeth C, Pratta, Michael A, Tortorella, Micky, Magolda, Ronald L, Newton, Robert, Qian, MingXin, Ribadeneira, Maria D, Christ, David, Wexler, Ruth R, Decicco, Carl P
• Format: Journal Article
• Language: English
• Published: American Chemical Society 11.10.2001
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm015533c

A pharmacophore model of the P1‘ site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1‘ group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2‘) to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.