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

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. 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 IC 50 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.