188728-68-9Relevant academic research and scientific papers
SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability
Gao, Donghong Amy,Xiong, Zhaoming,Heim-Riether, Alexander,Amodeo, Laura,August, E. Michael,Cao, Xianhua,Ciccarelli, Leonard,Collins, Brandon K.,Harrington, Kyle,Haverty, Kathleen,Hill-Drzewi, Melissa,Li, Xiang,Liang, Shuang,Margarit, Steluta Mariana,Moss, Neil,Nagaraja, Nelamangala,Proudfoot, John,Roman, Rene,Schlyer, Sabine,Keenan, Lana Smith,Taylor, Steven,Wellenzohn, Bernd,Wiedenmayer, Dieter,Li, Jun,Farrow, Neil A.
scheme or table, p. 5039 - 5043 (2010/10/18)
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1′ pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
Squaric acid-based peptidic inhibitors of matrix metalloprotease-1
Onaran, M. Burak,Comeau, Anthony B.,Seto, Christopher T.
, p. 10792 - 10802 (2007/10/03)
A series of squaric acid-peptide conjugates were synthesized and evaluated as inhibitors of MMP-1. The cyclobut-3-enedione core was substituted at the 3-position with several functional groups, such as -N(alkyl)OH, -NHOH, and -OH, that are designed to bind to the zinc atom in the active site of the metalloprotease. The 4-position of the cyclobut-3-enedione was derivatized with mono- or dipeptides that are designed to bind in the S1′ and S2′ subsites of the enzyme, and position the metal chelating group appropriately in the active site for binding to zinc. Positional scanning revealed that -N(Me)OH provided the highest level of inhibition among the chelating groups that were tested, and Leu-Tle-NHMe was the preferred amino acid sequence. A combination of these groups yielded an inhibitor with an IC50 value of 95 μM. For one inhibitor, conversion of one of the carbonyl groups on the cyclobut-3-enedione core to a thiocarbonyl group resulted in a 18-fold increase in potency, and yielded a compound with an IC50 value of 15 μM.
Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: An examination of the subsite pocket
Yamamoto, Minoru,Tsujishita, Hideki,Hori, Noriyuki,Ohishi, Yuichi,Inoue, Shintaro,Ikeda, Shoji,Okada, Yasunori
, p. 1209 - 1217 (2007/10/03)
The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (ΔMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an α-branched alkyl group is critical for the binding toward ΔMT1, while the introduction of a bulky group at the α-position of hydroxamic acid seems to diminish the activity against ΔMT1. Summation of the data on the sensitivity of ΔMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of ΔMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' α-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against ΔMT1 over MMP-1, but no selectivity between ΔMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
