title: Potent and selective aggrecanase inhibitors containing cyclic P1 substituents.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.forename: Ruowei
authors.initials: R
authors.lastname: Mo
authors.forename: Dayton T
authors.initials: DT
authors.lastname: Meyer
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
authors.forename: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Micky D
authors.initials: MD
authors.lastname: Tortorella
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Arner
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Ron L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: 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
chemical_list: D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D007527:Isoenzymes; D011480:Protease Inhibitors; D010450:Endopeptidases; C083641:aggrecanase