Zinc-binding groups modulate selective inhibition of MMPs.
The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In an effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were evaluated using an isolated perfused rat heart system. Hearts were subjected to ischemia reperfusion injury, and recovery of contractile function was examined. In this model, only one of the two MMPi showed significant and sustained heart recovery, demonstrating that the choice of ZBG can have a significant effect in a relevant pathophysiological endpoint.
Agrawal
Arpita
A
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Romero-Perez
Diego
D
Jacobsen
Jennifer A
JA
Villarreal
Francisco J
FJ
Cohen
Seth M
SM
D000818:Animals; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases; D015032:Zinc