Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents
Graphical abstract
1-Alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives were synthesized and evaluated for their T-type Ca2+ channel inhibitory activity.
Introduction
Intracellular Ca2+ is known to play an important role in various cellular functions, and Ca2+ channels on the cell membrane rigorously regulate concentration by influx of Ca2+. Voltage-gated calcium channels are located in the nervous, endocrine, cardiovascular, and skeletal systems and are modulated by membrane potential.1 This series of Ca2+ channels is divided into various subtypes based on functional and pharmacological properties: high-voltage-activated channels which can be subdivided into L-, N-, P/Q-, and R-types require a strong depolarization to be activated, whereas low-voltage-activated or T-type (transient) channels are first activated by a relatively weak depolarization and then rapidly inactivated.2 Of these two subtypes, the T-type-channels are believed to contribute to the regulation of cardiovascular activities such as heart rate (HR), arterial and venous smooth muscle intervention, and tone.3 As such, these types of channel are regarded as important therapeutic targets for treating various cardiovascular diseases such as hypertension, angina, heart failure, and arrhythmia.
Mibefradil (1), the first launched T-type Ca2+ channel blocker, demonstrated superior efficacy over the traditional L-type Ca2+ channel blockers in treating hypertension and angina, and the adverse effects often seen by the treatment with L-type Ca2+ channel blockers were not reported (such as reflex tachycardia, negative inotropy, vasoconstrictive hormone release, and peripheral edema).4 However, despite its excellent antihypertensive effect, mibefradil was withdrawn from the market in 1998 due to drug–drug interactions.5 Since then, substantial research efforts have been made in identifying new types of T-type Ca2+ channel blockers.6
In our research on novel antihypertensive drugs, we previously reported on the utility of novel tetrahydroisoquinoline derivatives.7 We subsequently conducted high-throughput screening (HTS) using Astellas chemical library to identify a new series of T-type Ca2+ channel blockers. On examination of inhibitory activities against T-type Ca2+ channels, we identified compound 2 (Fig. 1), which showed moderate inhibitory activity (IC50 = 0.32 μM) and a similar bradycardic profile to mibefradil (Table 1).
Here, we describe the synthesis, structure–activity relationship, and pharmacological properties of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel T-type Ca2+ channel blocking agents.
Section snippets
Chemistry
The preparation of 1-benzyl-N-{[1-(4-fluorophenyl)cycloalkyl]methyl}piperidinecarboxamide derivatives is outlined in Scheme 1. 4-Fluorophenylacetonitrile 3 was first transformed to carboxamide 4a–f in a three-step sequence consisting of dialkylation of the benzylic position with dibromoalkane, hydrogenation of the nitrile group in the presence of Raney–Ni, and condensation with tert-butoxycarbonyl(Boc)-protected piperidinecarboxylic acid in the presence of
Results and discussion
In the present study, we first investigated the effect of changing the substitution pattern of the piperidine ring, as shown in Table 2. The parent compound 5a showed moderate inhibitory activity against T-type Ca2+ channels, with an IC50 value of 0.51 μM. The 3-piperidyl derivative 5b exhibited an approximately twofold decrease in activity compared to 5a, while the 2-piperidyl derivative 5c was found to be less effective than 5b. These results indicated that the substitution position on the
Conclusion
A series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide were synthesized and evaluated. Structure–activity relationship studies of this novel class of compounds revealed that benzylic dialkyl substituents played an important role for a potent inhibitory activity against T-type Ca2+ channels. Of this series, N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) exerted an antihypertensive effect without undesirable reflex tachycardia when
Chemistry
1H NMR spectra were obtained on a JEOL JNM-EX400 spectrometer and the chemical shifts are expressed in δ (ppm) values with tetramethylsilane as an internal standard. Abbreviations of 1H NMR signal patterns are as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; br, broad. Mass spectra were obtained on a JEOL JMS-DX300 or HITACHI M-80 spectrometer. Column chromatography on silica gel was performed with Kieselgel 60 (E. Merck).
Acknowledgements
We thank Dr. Fukushi Hirayama for his helpful support in preparing this manuscript. We are also grateful to Dr. Hironori Harada, Dr. Masakazu Imamura, and Mr. Kyoichi Maeno for their useful advice. Finally, we wish to thank Mr. Kazuhiko Mizukami, Miss Yuriko Komiya, Dr. Noriyasu Kanie, Mr. Satoshi Konagai, and Mr. Eisaku Yamamoto for performing the biological experiments, and the members of the Division of Analytical Science Laboratories for elemental analysis and spectral measurements.
References and notes (10)
- et al.
J. Org. Chem.
(2009) J. Org. Chem.
(1982)Br. J. Pharmacol.
(2006)- et al.
Pharmacol. Rev.
(2005)et al.Can. J. Anaesth.
(2002) Physiol. Rev.
(2003)