Novel pyrazolo[1,5-a]pyrimidines as c-Src kinase inhibitors that reduce IKr channel blockade

To improve the in vitro potency of the c-Src inhibitor 1a and to address its hERG liability, a structure–activity study was carried out, focusing on two regions of the lead compound. The blockade of the delayed cardiac current rectifier K+ (IKr) channel was overcome by replacing the ethylenediamino group with an amino alcohol group at the 7-position. In addition, modifying the substituents at the 5-position and the side chain groups on the amino alcohols at the 7-position enhanced the intracellular c-Src inhibitory activity and increased central nervous system (CNS) penetration. In the present study, 6l exhibited significant in vivo efficacy in a middle cerebral artery (MCA) occlusion model in rats.

We prepared pyrazolo[1,5-a]pyrimidine derivatives that were potent c-Src kinase inhibitors. Modification of the ethylenediamino group at the 7-position of the lead compound 1a to an amino alcohol group resulted in reduced IKr channel inhibition. In particular, 6l showed significant neuroprotective effects in a stroke model.Figure optionsDownload as PowerPoint slide