Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors
A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC50 values of 290 and 25 nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.
Jones, Matthew A.,Morton, James D.,Coxon, James M.,McNabb, Stephen B.,Lee, Hannah Y.-Y.,Aitken, Steven G.,Mehrtens, Janna M.,Robertson, Lucinda J.G.,Neffe, Axel T.,Miyamoto, Shigeru,Bickerstaffe, Roy,Gately, Karl,Wood, Jacqueline M.,Abell, Andrew D.
p. 6911 - 6923
(2008/12/22)
5-sulfonamido-substituted indolinone compounds as protein kinase inhibitors
The present invention relates to 5-sulfonamido substituted indolinones that modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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Page/Page column 16
(2010/02/08)
Sulfonamide substituted indolinones as inhibitors of DNA dependent protein kinase (DNA-PK)
The present invention relates generally to the field of radiosensitizing agents which are capable of enhancing radiotherapy by inhibiting DNA-PK (DNA-protein kinase). In particular, it relates to sulfonamide substituted indolinones which inhibit DNA-PK.
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Page 12
(2010/02/10)
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