SMALL MOLECULE INHIBITORS OF ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE WITH POTENTIAL ANTICANCER ACTIVITY
The present invention generally relates to inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), in particularly to compounds that inhibit Icmt activity and pharmaceutical compositions thereof. The invention also relates to methods of disease treatment using the same.
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Page/Page column 32
(2011/02/24)
Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase
The enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) plays an important role in the post-translational modification of proteins that are involved in the regulation of cell growth. The indole acetamide cysmethynil is by far the most potent and widely investigated Icmt inhibitor, but it has modest antiproliferative activity and may have pharmacokinetic limitations due to its lipophilic character. We report here that cysmethynil can be structurally modified to give analogues that are as potent in inhibiting Icmt but with significantly greater antiproliferative activity. Key modifications were the replacement of the acetamide side chain by tertiary amino groups, the n-octyl side chain by isoprenyl and the 5-m-tolyl ring by fluorine. Moreover, these analogues have lower lipophilicities that could lead to improved pharmacokinetic profiles.
Go, Mei-Lin,Leow, Jo Lene,Gorla, Suresh Kumar,Schüller, Andreas Peter,Wang, Mei,Casey, Patrick J.
experimental part
p. 6838 - 6850
(2010/11/18)
Aryl-indolyl maleimides as inhibitors of CaMKIIδ. Part 2: SAR of the amine tether
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin-dependant kinase. Inhibitory activities against the enzyme ranged from 34 nM to >20 μM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Aryl-indolyl maleimides as inhibitors of CaMKIIδ. Part 1: SAR of the aryl region
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34 nM to >20 μM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions.
INHIBITORS OF ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE
The present invention relates, in general, to isoprenylcysteine carboxyl methyltransferase (Icmt) and, in particular, to inhibitors of Icmt and to methods of disease treatment using same.
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Page/Page column 26-27
(2008/06/13)
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