Potent P1' biphenylmethyl substituted aggrecanase inhibitors.
A series of cis-1(S)2(R)-amino-2-indanol based compounds with a biphenylmethyl group at the P1' position was found to be potent aggrecanase inhibitors. Both compounds 2j and 2n possessed very high aggrecanase affinity (IC(50)=1.5nM), and showed excellent selectivity over MMP-1 and MMP-9, with moderate selectivity against MMP-2.
Yao
Wenqing
W
Department of Chemistry, Bristol-Myers Squibb Pharma Company, Experimental Station, Wilmington, DE 19880-0500, USA. wenping.yao@dupontpharma.com
Chao
Michael
M
Wasserman
Zelda R
ZR
Liu
Rui Qin
RQ
Covington
Maryanne B
MB
Newton
Robert
R
Christ
David
D
Wexler
Ruth R
RR
Decicco
Carl P
CP
D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008666:Metalloendopeptidases / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D018501:Antirheumatic Agents; D001713:Biphenyl Compounds; D011480:Protease Inhibitors; D010450:Endopeptidases; D008666:Metalloendopeptidases; C083641:aggrecanase