Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors

doi:10.1016/j.bmc.2013.08.041

Bioorganic & Medicinal Chemistry

Volume 21, Issue 21, 1 November 2013, Pages 6466-6476

https://doi.org/10.1016/j.bmc.2013.08.041 Get rights and content

Abstract

Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations.

Graphical abstract

Introduction

As the most common sustained form of arrhythmia, atrial fibrillation (AF) affects a large and growing population,1, 2, 3, 4 some further projections⁵ indicate that the morbidity of AF will at least double in the next 5 decades with the ageing population and will lead to substantial mortality of stroke and heart failure.6, 7

Antiarrhythmic medications remain a mainstay in the treatment of AF.⁸ Currently the antiarrhythmic agents,⁹ such as dofetilide and sotalol, are limited in efficacy and considerable risks2, 10 for their unselective blockade of the potassium currents in both atrial and ventricular myocytes.¹¹ One interesting potential target is the ultra-rapid potassium channel (I_Kur, encoded by Kv1.5 gene) which is functionally expressed in the atrium but not ventricle in humans,12, 13, 14 suggesting Kv1.5 potassium channel as a novel selective target for the treatment of AF.¹⁵

Our previous studies16, 17 reported a pharmacophore model of Kv1.5 (Fig. 1) that was made up of one hydrogen bond acceptor, one aromatic ring, and two hydrophobic groups. After structure-based virtual screening of the compounds from the Maybridge database, in silico druglike property prediction and electrophysiological evaluation were undertaken,18, 19 leading to a lead compound RH01617 with outstanding Kv1.5 inhibitory activity (Fig. 1). Herein, with the aim of carefully investigating the structure–activity relationship (SAR), three series of derivatives containing 30 compounds were designed, synthesized and bioevaluated. Among them, compounds IIIi and IIIl showed potent activity and were chosen for further pharmacodynamic evaluations. The results showed that compound IIIl possessed remarkable selectivity Kv1.5 potassium channel activity over hERG (human ether-a-go-go gene) potassium channel and sodium channel, while the atrial selective profile was also proved in the animal model in vitro.

Section snippets

Chemistry

Compounds Ia–Ii were prepared from methyl tryptophan ester hydrochloride and commercially available or synthesized sulfonyl chloride derivatives (Scheme 1). Starting from 4-hydroxybenzenesulfonate and alkyl bromide, compounds 2a–2e were obtained via substitution and acylation reaction. Compounds 3a–3b were obtained from tryptophan or phenylalanine and CH₃OH in the presence of SOCl₂. Reaction of 2a–2e with 3a–3b in CH₂Cl₂ provided the target compounds Ia–Ii. Compound Ia was hydrolyzed by LiOH (1

Conclusion

Drug targeted cardiac Kv1.5 channel is supposed to have a safety advantage over current market drugs. In this study, we have designed and synthesized 29 novel compounds modified from the lead compound Ia which was identified from virtual screening we previously reported, aiming at discovering potent and selective Kv1.5 inhibitors. Structural modifications mainly addressing the side chain of phenyl, ester group, coupling chain and N-substituents at indolyl enabled modulation of Kv1.5 inhibitory

General methods, materials, and spectroscopic details

Melting points were measured with a Melt-Temp II instruments. IR spectra were recorded on a Nicolet Impact 410 spectrometer. EI-MS was recorded Shimadzu GC–MS 2050 apparatus; ESI-MS was recorded on Agilent 1100 LC/MSD (70 ev) spectrometers. ¹H NMR and ¹³C NMR spectra were recorded on Bruker AV-300 or AV-500 MHz instruments in DMSO-d₆ and CDCl₃ using tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported as d values (parts per million) relative to solvent peak. Coupling

Acknowledgments

The authors thank Dr. Gui-Rong Li (Department of Medicine and Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China) for providing the HEK293 cells in which Kv1.5 channels are stably expressed.

This work was supported by the Project Program of State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, the innovation Program for the Postgraduates in Jiangsu in 2012, National Major Science

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¹: These authors contributed equally to this work.

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Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

General methods, materials, and spectroscopic details

Acknowledgments

Lancet

Lancet

J. Mol. Graphics Modell.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Tetrahedron

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Int. J. Cardiol.

Nat. Rev. Drug Disc.

Europace

Expert Opin. Pharmacother.

QSAR Comb. Sci.

Circulation

Cleve. Clin. J. Med.

Europace

Expert Opin. Drug Saf.