Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2001-10, Vol.44 (21), p.3347-3350

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2001

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.