Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor

•Identified 2-amino-4-pyrazolecyclopentylpyrimidine scaffold as IGF-1R inhibitor.•Compound 6f exhibit promising cell based activity across a panel of cell lines.•Compound 6f may serve as a lead for developing newer anti-cancer agents.

A series of novel 2-amino-4-pyrazolecyclopentylpyrimidines have been prepared and evaluated as IGF-1R tyrosin kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 2- amino ring, 4-pyrazolo moieties and size of fused saturated ring with the central pyrimidine core. A stepwise optimization by combination of active fragments led to discovery of compound 6f and 6k, two structures with IGF-1R IC50 of 20 nM and 10 nM, respectively. 6f was further profiled for its anti cancer activity across various cell lines and pharmacokinetic studies in Sprague Dawley rats.

Graphical abstractDesign, synthesis, and biological evaluation of novel 2-amino-4-pyrazolecyclopentylpyrimidines as IGR-1R tyrosin kinase inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide