Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors
| Autor: | W, Yao, Z R, Wasserman, M, Chao, G, Reddy, E, Shi, R Q, Liu, M B, Covington, E C, Arner, M A, Pratta, M, Tortorella, R L, Magolda, R, Newton, M, Qian, M D, Ribadeneira, D, Christ, R R, Wexler, C P, Decicco |
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| Rok vydání: | 2001 |
| Předmět: |
Models
Molecular Administration Oral Biological Availability Stereoisomerism Hydroxamic Acids Structure-Activity Relationship Dogs Matrix Metalloproteinase 8 Matrix Metalloproteinase 9 Drug Design Endopeptidases Animals Matrix Metalloproteinase 2 Protease Inhibitors Asparagine Matrix Metalloproteinase 1 Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 44(21) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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