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

doi:10.1016/j.bmc.2009.11.014

Bioorganic & Medicinal Chemistry

Volume 18, Issue 1, 1 January 2010, Pages 111-116

https://doi.org/10.1016/j.bmc.2009.11.014 Get rights and content

Abstract

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.

Graphical abstract

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.

Introduction

Silicon and carbon are members of group IV of Periodic Table of the Element and share some similarities in several aspects. Due to these similarities, in general, the silicon-substituted derivatives share the same pharmacological mode of action as the corresponding carbon analogues. However, these two elements also have some subtle differences in molecular size, shape, electronegativity, and lipophilicity. These differences can lead to marked alterations in the physicochemical and biological properties of silicon-containing analogues.¹ Thus, incorporation of silicon into biologically pre-validated drug scaffolds represents an excellent tetrahedral isostere of carbon. This silicon switch approach for safe marketed drugs is cost-effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods.²

Recently, we have reported the synthesis and biological evaluation of 1,3-dibenzylthioureas as novel TRPV1 antagonist (Fig. 1).³ TRPV1 is a ligand-gated nonselective cation channel vanilloid receptor 1 (VR1) with high Ca²⁺ permeability,⁴ emerging as a novel target for the treatment of pain.⁵ Based on the premise that direct blockage of TRPV1 by its antagonists could be a promising way of silencing pain signaling pathways,⁶ extensive works have been done to develop new TRPV1 antagonists during the past decade.⁷ We have also reported the dibenzylthiourea analogues including MK-056 (1),^3a SC-0030 (2),^3b and ATC-120 (3),^3c which exhibit highly potent competitive TRPV1 antagonist effects, as well as their structure–activity relationship (SAR).⁸ From the SAR study, it revealed that 4-tert-butyl group of MK-056 derivatives is essential for potency. All attempts to replace tert-butyl groups of MK-056 series to other alkyl groups resulted in weakening their potencies.⁹

In searching for opportunities to exploit the benefits of silicon in TRPV1 (transient receptor potential vanilloid subfamily 1) research, we tried silicon switch approach to search for new TRPV1 antagonist that have beneficial pharmacodynamic or pharmacokinetic properties and novel IP position. In this context, we decided to investigate the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series.

Section snippets

Chemistry

Trimethylsilanyl, ethyldimethylsilanyl, and triethylsilanyl groups were chosen as bioisosteres of t-butyl group. MK-056 (1), SC-0030 (2) and ATC-120 (3) were also chosen as reference compounds in order to clarify the sila-substitution effect. It is because that these three compounds represent the most important scaffolds in 1,3-dibenzylthioureas with high antagonist activity. Thus, target compounds in this study were the trialkylsilanyl derivatives of MK-056 (1), SC-0030 (2) and ATC-120 (3).

Conclusion

In summary, we have designed and synthesized a series of silicon analogues of the MK-056 by silicon switch approach to search for new TRPV1 antagonist. The synthesized seven silicon-substituted 1,3-dibenzylthioureas 13a–c, 14a–c and 15 were tested for their antagonist activities on TRPV1 by ⁴⁵Ca²⁺-influx assay using neonatal rat cultured spinal sensory neurons. Compound 13a, with a 4-positioned trimethylsilanyl group on the B ring in place of tert-butyl group, exhibited the most potent

General method

The melting points were obtained using Büchi 535 melting point apparatus and were uncorrected. Optical rotations were measured on a JASCO DIP 1000 digital polarimeter. ¹H NMR and ¹³C NMR spectra were obtained on a Varian Inova 400 spectrometer and the chemical shifts are reported as values in parts per million (δ) relative to tetramethylsilane (TMS) as an internal standard. The infrared spectra (IR) were recorded on a JASCO FT/IR-430 spectrophotometer. Low resolution mass spectra were obtained

Acknowledgements

This research was supported by the SRC program of KOSEF (Research Center for Women’s Diseases) and by the grant from AmorePacific Corporation.

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

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

General method

Acknowledgements

Toxicol. Appl. Pharmacol.

ChemBioChem

ChemMedChem

Toxicol. Appl. Pharmacol.

ChemMedChem

Nat. Rev. Drug Disc.

Nature

Pfluegers Arch.

Eur. J. Biochem.

Biochem. Pharmacol.

Drug Discovery Today

Trends Mol. Med.

Br. J. Anaesth.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Curr. Opin. Drug Disc. Dev.

Drug Discovery Today

Exp. Opin. Invest. Drugs

Drug Dev. Res.

Curr. Opin. Drug Disc. Dev.