Non Atpcompetitive Inhibitors

SAR and lead optimization efforts to mitigate metabolic liabilities due to the catechol rings led to some moderately potent benzoxazolone analogs 32a-c [73]. No selectivity over IR was observed. Replacement of both catechols with benzoxazolone rings led to inactive compounds.

To date, none of the synthetic catechols or their close analogs discussed above have progressed into clinical development. The naturally occurring bis-catechol, nordihydroguaiaretic acid, 33 (NDGA, INSM-18), has advanced to phase II clinical trials using continuous oral dosing for the treatment of prostate cancer [75-77]. NDGA inhibits IGF-1R phosphorylation of a synthetic nonspecific tyrosine kinase substrate and proliferation of MCF-7 breast cell line with an IC5o of 0.9 and 24.6 p.M respectively. Some early positive clinical data is now emerging from the prostate trial with respect to reduction in prostate-specific antigen (PSA) levels and delay in PSA doubling time in patients. Doses up to 2,500 mg/ day are tolerated with minimal toxic effects. NDGA has Her-2 receptor kinase and 15-lipoxygenase inhibitory activity. Although there is no direct mention of 33 being a non ATP-competitive IGF-1R inhibitor, it is a non ATP-competitive inhibitor of FGFR3 tyrosine kinase [78].

0 0

Post a comment