Design and Synthesis of a Series of (2R)-N4-Hydroxy-2-(3-hydroxybenzyl)-N- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl]butanediamide Derivatives as …
W Yao, ZR Wasserman, M Chao, G Reddy… - Journal of medicinal …, 2001 - ACS Publications
W Yao, ZR Wasserman, M Chao, G Reddy, E Shi, RQ Liu, MB Covington, EC Arner…
Journal of medicinal chemistry, 2001•ACS PublicationsA 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-(1 S)(2 R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2 ')
to conformationally constrain 2. Further optimization resulted in compound 11, a potent …
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-(1 S)(2 R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2 ')
to conformationally constrain 2. Further optimization resulted in compound 11, a potent …
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.
ACS Publications