Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.
The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.
Cheng
M
M
Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
De
B
B
Almstead
N G
NG
Pikul
S
S
Dowty
M E
ME
Dietsch
C R
CR
Dunaway
C M
CM
Gu
F
F
Hsieh
L C
LC
Janusz
M J
MJ
Taiwo
Y O
YO
Natchus
M G
MG
Hudlicky
T
T
Mandel
M
M
D000818:Animals; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011392:Proline