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.
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.
Yao
W
W
The DuPont Pharmaceuticals Company, Chemical and Physical Sciences, Inflammatory Diseases Research, Drug Metabolism and Pharmacokinetics Division, Experimental Station, Wilmington, Delaware 19880-0500, USA. Wenqing.yao@dupontpharma.com
Wasserman
Z R
ZR
Chao
M
M
Reddy
G
G
Shi
E
E
Liu
R Q
RQ
Covington
M B
MB
Arner
E C
EC
Pratta
M A
MA
Tortorella
M
M
Magolda
R L
RL
Newton
R
R
Qian
M
M
Ribadeneira
M D
MD
Christ
D
D
Wexler
R R
RR
Decicco
C P
CP
D000284:Administration, Oral; D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; C438585:N-hydroxy-2-(cyclopropylmethylamino)-4-((2-hydroxyindan-1-yl)amino)-3-((3-hydroxyphenyl)methyl)-4-oxobutanamide; D011480:Protease Inhibitors; D001216:Asparagine; D010450:Endopeptidases; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; C083641:aggrecanase