Potent and selective aggrecanase inhibitors containing cyclic P1 substituents.
Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
Cherney
Robert J
RJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
Mo
Ruowei
R
Meyer
Dayton T
DT
Wang
Li
L
Yao
Wenqing
W
Wasserman
Zelda R
ZR
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Tortorella
Micky D
MD
Arner
Elizabeth C
EC
Qian
Mingxin
M
Christ
David D
DD
Trzaskos
James M
JM
Newton
Robert C
RC
Magolda
Ron L
RL
Decicco
Carl P
CP
D000818:Animals; D002417:Cattle; D004285:Dogs; D010450:Endopeptidases / Q000378:metabolism*; D006207:Half-Life; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D007527:Isoenzymes; D011480:Protease Inhibitors; D010450:Endopeptidases; C083641:aggrecanase