Martin P. Maguire

The synthesis and SAR of new 4-(N-alkyl-N-phenyl)amino-6,7-dimethoxyquinazolines and 4-(N-alkyl-N-phenyl)aminopyrazolo[3,4-d]pyrimidines, inhibitors of CSF-1R tyrosine kinase activity

Abstract We have identified moderately potent and selective inhibitors of CSF-1R tyrosine kinase activity.1 A preliminary SAR study resulted in the identification of compounds 11 and 20 as the most potent analogues in the series (IC50 = 0.18 μM). The 3-D-conformation of the 4-(N-alkyl-N-phenyl)-aminoquinazolines has been proposed to be important to the overall selectivity and activity.

Inhibition kinetics and selectivity of the tyrosine kinase inhibitor erbstatin and a pyridone-based analogue

The inhibition mechanisms of the epidermal growth factor (EGF) receptor tyrosine kinase and the cAMP-dependent kinase activities by erbstatin and its analogue, RG 14921, were studied by kinetic analysis. Both compounds were slow-binding inhibitors of the EGF receptor kinase. Erbstatin inhibited the EGF receptor kinase as a partial competitive inhibitor with respect to both ATP and the peptide substrate, suggesting that it binds at a site distinct from the ATP and peptide binding sites of the enzyme, and thus lowers the binding affinities of the enzyme for both substrates. In contrast, the analogue RG 14921 inhibited EGF receptor kinase activity as a non-competitive inhibitor with respect to both ATP and the peptide substrate. The distinct modes of inhibition by structurally related compounds suggest a dynamic and possibly extended structure of the catalytic center of the kinase domain of the receptor. Erbstatin and RG 14921 exerted similar effects on cAMP-dependent protein kinase activity. In this system, both compounds displayed potent inhibition and acted by a mode of competitive inhibition with respect to ATP and non-competitive with the peptide substrate.