Silicon switch approach in TRPV1 antagonist MK-056 and its analogues

In searching for opportunities to exploit the benefits of silicon in TRPV1 research, we tried to investigate the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series. Compound 13a, with a 4-positioned trimethylsilanyl group on the B ring in place of tert-butyl group, exhibited the most potent antagonist activity with IC50 values of 0.15 μM, which is almost equipotent with that of MK-056. This is the first example that tert-butyl group on MK-056 series can be replaced to the other substituent without loss of activity.

A series of silicon analogues of the MK-056 were designed and synthesized by silicon switch approach to search for new TRPV1 antagonist. tert-Butyl on MK-056 can be replaced to trimethylsilanyl without loss of activity.Figure optionsDownload as PowerPoint slide