Sultam hydroxamates as novel matrix metalloproteinase inhibitors.
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
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
Hardman
Karl D
KD
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Wasserman
Zelda R
ZR
Christ
David D
DD
Trzaskos
James M
JM
Newton
Robert C
RC
Decicco
Carl P
CP
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse