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
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 mo...
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Published in | Journal of medicinal chemistry Vol. 44; no. 21; pp. 3347 - 3350 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
11.10.2001
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Abstract | 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. |
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AbstractList | 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. |
Author | Reddy, Gade Pratta, Michael A Liu, Rui-Qin Newton, Robert Arner, Elizabeth C Chao, Michael Christ, David Yao, Wenqing Qian, MingXin Decicco, Carl P Wasserman, Zelda R Covington, Maryanne B Magolda, Ronald L Wexler, Ruth R Ribadeneira, Maria D Tortorella, Micky Shi, Eric |
Author_xml | – sequence: 1 givenname: Wenqing surname: Yao fullname: Yao, Wenqing – sequence: 2 givenname: Zelda R surname: Wasserman fullname: Wasserman, Zelda R – sequence: 3 givenname: Michael surname: Chao fullname: Chao, Michael – sequence: 4 givenname: Gade surname: Reddy fullname: Reddy, Gade – sequence: 5 givenname: Eric surname: Shi fullname: Shi, Eric – sequence: 6 givenname: Rui-Qin surname: Liu fullname: Liu, Rui-Qin – sequence: 7 givenname: Maryanne B surname: Covington fullname: Covington, Maryanne B – sequence: 8 givenname: Elizabeth C surname: Arner fullname: Arner, Elizabeth C – sequence: 9 givenname: Michael A surname: Pratta fullname: Pratta, Michael A – sequence: 10 givenname: Micky surname: Tortorella fullname: Tortorella, Micky – sequence: 11 givenname: Ronald L surname: Magolda fullname: Magolda, Ronald L – sequence: 12 givenname: Robert surname: Newton fullname: Newton, Robert – sequence: 13 givenname: MingXin surname: Qian fullname: Qian, MingXin – sequence: 14 givenname: Maria D surname: Ribadeneira fullname: Ribadeneira, Maria D – sequence: 15 givenname: David surname: Christ fullname: Christ, David – sequence: 16 givenname: Ruth R surname: Wexler fullname: Wexler, Ruth R – sequence: 17 givenname: Carl P surname: Decicco fullname: Decicco, Carl P |
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Title | 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 |
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