Elsevier

Bioorganic & Medicinal Chemistry

Volume 22, Issue 21, 1 November 2014, Pages 6071-6088
Bioorganic & Medicinal Chemistry

Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists

https://doi.org/10.1016/j.bmc.2014.08.034Get rights and content

Abstract

Herein we describe the design, synthesis, and structure–activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((−)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists.

Introduction

Orexin/hypocretin receptors (OXRs) are a Class A of G-protein-coupled receptors (GPCRs) that mediate the action of two endogenous neuropeptide ligands known as orexin A and orexin B (33 and 28 amino acids long, respectively), which are also known as hypocretin 1 and hypocretin 2. Within the central nervous system, these peptides are exclusively produced in a small cluster of neurons in the posterior and lateral hypothalamus, from where they project widely throughout the central nervous system.1, 2, 3 The orexin signaling system is involved in multiple functions related to feeding behavior, metabolism, sleep/arousal states, and brain reward mechanisms. Indeed, a number of genetic and pharmacological studies have indicated that the orexin system plays a key role in regulating the sleep/wake cycle.4, 5 Abnormalities in orexin signaling, such as orexin peptide deficiency or a lack of OXRs, produce a narcolepsy–cataplexy-like phenotype in mice.6, 7 Moreover, narcolepsy–cataplexy syndrome in humans has been associated with diminished levels of orexin-A in the cerebrospinal fluid and with a near or total loss of orexinergic neurons.8, 9, 10 There are also reports that blocking the orexin/hypocretin receptor 2 (OX2R) pathway results in a noticeable sleep phenotype, while blocking the orexin/hypocretin receptor 1 (OX1R) pathway produces a moderate sleep phenotype but contributes to sleep stabilization, suggesting that both receptors are involved in sleep/wake regulation.11, 12, 13, 14, 15, 16, 17, 18 Despite this contextual evidence, the precise contributions of OX1R and OX2R signaling pathways to various physiological processes have not been completely elucidated. Therefore, further studies are needed to characterize dual orexin antagonists and selective orexin antagonists for potential use as sleep drugs.

Given the therapeutic potential of the orexin system, orexin receptor antagonists have been a significant focus of drug discovery research, primarily for treating insomnia.19, 20, 21, 22, 23, 24 The best studied dual orexin antagonist to date is almorexant (1),25 which was developed by Actelion/GlaxoSmithKline for the treatment of insomnia but discontinued at the phase III clinical trial stage. Another compound developed by GlaxoSmithKline26 SB-649868 (2), was evaluated in phase II clinical trials earlier than almorexant but was not advanced to a phase III trial. Another dual orexin antagonist developed by Merck, suvorexant (3), is currently being reviewed by the United States Food and Drug Administration (FDA) under a New Drug Application submitted in 2012 (Fig. 1).27, 28

Herein we report the design, synthesis, structure–activity relationships, and animal model efficacy for a series of novel orally active orexin receptor antagonists.

Section snippets

Seed generation of orexin antagonists from trigger compound

While pursuing another lead discovery program, we identified compound 4 (Fig. 2) and discovered that it is an antagonist of OX2R. This finding shifted our focus to optimizing 4 as a potential trigger for insomnia treatment. We initially investigated the SAR at the right R position (Table 1) and found that the introduction of a benzyl ketone (5) led to decreased binding affinity. We next synthesized amine 6, which could be readily prepared from a common aldehyde intermediate, and we found that 6

Chemistry

The general synthetic pathway for the analogs is described in Scheme 1. Cyclopropane ring formation was accomplished by reacting a substituted aryl acetonitrile 11 with racemic epichlorohydrin to give lactone 12.24 Reduction of the lactone with sodium borohydride gave cis-diol 13. After protection of 13 with TBDPS-Cl to give 14, Mitsunobu reaction of the corresponding alcohol with various phenols led to the production of compounds 15ag, which were deprotected using TBAF and oxidized (Swern and

Pharmacology and in vitro SAR

Our initial SAR evaluation focused on understanding the importance of the 3,4-diOMe-Ph group. Specifically, we designed several analogs to determine the importance of HBAs on OX1R/OX2R binding activity. Table 3 summarizes the results obtained for the derivatives. Notably, although the substitution of a 2-pyridine (2-Py) for the phenyl C-ring (compound 19) decreased the binding affinity slightly compared to that of 7, the 2-Py derivative has superior physicochemical property and is expected to

Conclusion

We have described a novel series of orexin receptor antagonists derived from a compound identified in another discovery program. Our optimization effort produced a promising seed compound (7) that has low nanomolar binding potency for OX2R and OX1R. Through further optimization, we elucidated the crucial SAR for each region of the seed compound. Thus, we identified a compound (33b) that has improved in vitro binding affinity and reduced lipophilicity compared to those of the seed compound 7. We

General methods

1H and 13C NMR spectra were recorded on a Bruker Avance spectrometer (operating at 600 MHz) or Varian Model 500 Unity Inova (operating at 500 MHz), Varian Mercury 400 spectrometer (operating at 400 MHz). 13C NMR spectra were recorded on a Bruker Avance spectrometer (operating at 150 MHz). Chemical shifts were calculated in ppm (δ) from the residual CHCl3 signal at (δH) 7.26 ppm and (δC) 77.0 ppm in CDCl3. High-resolution mass spectra (HRMS) were recorded on a ThermoFisherScientific LTQ-Orbitrap XL

Acknowledgments

The authors would like to thank the colleagues who helped generate data reported in this manuscript. In particular, special thanks to Eri Ena, Satoko Sasaki, Masaki Kato, and Yumi Yokoyama for NMR and HRMS analyses, and to Misako Watanabe and Kazuya Nagaoka for chemoinformatics support.

References and notes (35)

  • T. Sakurai et al.

    Cell

    (1998)
  • R.M. Chemelli et al.

    Cell

    (1999)
  • J.T. Willie et al.

    Neuron

    (2003)
  • T.C. Thannickal et al.

    Neuron

    (2000)
  • S. Nishino

    Handb. Clin. Neurol.

    (2011)
  • M.A. Akanmu et al.

    Brain Res.

    (2005)
  • B.A. Kummangal et al.

    Behav. Brain Res.

    (2013)
  • L.P. Stasi et al.

    Bioorg. Med. Chem. Lett.

    (2013)
  • T. Fujimoto et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • L. De Lecea et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • A.N. Van den Pol et al.

    J. Neurosci.

    (1998)
  • C.T. Beuckmann et al.

    J. Mol. Med. (Berl.)

    (2002)
  • C. Brisbare-Roch et al.

    Nat. Med.

    (2007)
  • C. Peyron et al.

    Nat. Med.

    (2000)
  • C. Dugovic et al.

    J. Pharmacol. Exp. Ther.

    (2009)
  • M.A. Steiner et al.

    ChemMedChem

    (2013)
  • P.J. Coleman et al.

    Expert Opin. Ther. Pat.

    (2010)
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