Elsevier

Bioorganic & Medicinal Chemistry

Volume 22, Issue 23, 1 December 2014, Pages 6694-6705
Bioorganic & Medicinal Chemistry

Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

https://doi.org/10.1016/j.bmc.2014.09.012Get rights and content

Abstract

The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8–10, while diverse leaving groups are tolerated for FAAH inhibitors.

Introduction

Endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) have been found in most mammalian tissues and they stimulate cannabinoid CB1 and CB2 receptor activity thereby modulating several physiological responses, including nociception, anxiety, and depression.1, 2 The two main enzymes involved in endocannabinoid degradation are monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Two additional endocannabinoid-hydrolyzing enzymes have recently been discovered: α/β-hydrolase domain containing serine hydrolases ABHD6 and ABHD12, which are described as complementary 2-AG-degrading enzymes in the brain.3 Inhibition of these enzymes leads to accumulation of endocannabinoids and inducement of cannabimimetic effects.4

FAAH is the primary AEA-degrading enzyme,5 but it is also capable of hydrolyzing other bioactive N-acylethanolamines (NAEs), such as N-palmitoylethanolamine (PEA),6 N-oleoylethanolamine (OEA)6 and the sleep-inducing lipid oleamide.7

Pharmacological inhibition of FAAH has been considered as potential therapeutic approach for the treatment of several nervous system disorders, including pain, inflammation, anxiety, and depression.2, 8, 9

MAGL inhibitors may have therapeutic potential in treatment of cancer and neuroinflammatory diseases. MAGL hydrolyzes 2-AG to arachidonic acid, from which cyclooxygenases can synthesize neuroinflammatory prostaglandins.10 Therefore, it is possible that inhibition of MAGL may be an alternative way to regulate prostaglandin production and to reduce inflammation in neurodegenerative diseases. In addition, MAGL has been shown to control lipid metabolism in cancer cells by promoting production of lipid molecules towards oncogenic lipid messengers.11

A large number of FAAH inhibitors have been described over the years, such as α-keto heterocycles, lactams, carbamates, and piperidine/piperazine based ureas.12 So far, the most promising irreversible FAAH inhibitors with respect to selectivity and potency are piperidine and piperazine urea compounds, such as PF-3845 and JNJ-1661010 (Fig. 1). The development of potent and selective MAGL inhibitors has been slower compared to that of FAAH due to only recent availability of X-ray crystal structural data.13, 14, 15 In the model by Sanofi-Aventis, the crystal structure of MAGL was built by complexing the enzyme with the piperazine triazole urea inhibitor SAR629.14 This structure was one starting point for our compound series of piperazine triazole urea compounds. Very recently, remarkable progress has been achieved in the discovery of potent and selective MAGL inhibitors. Cravatt and co-workers have reported MAGL selective piperidine carbamate based inhibitors JZL184 and KLM-29 and piperazine carbamate based dual FAAH–MAGL inhibitors, such as JZL195 (Fig. 1). Other very recently published piperidine/piperazine ureas are benzotriazol-1-yl carboxamides, such as ML30 (Fig. 1) by Lambert and co-workers16 and piperazine ureas (e.g., 60j) by Kono et al.17, 18 While writing this manuscript, Wilson and co-workers have reported radiosynthesis of carbamate- and urea-based MAGL inhibitors.19

In this work, we follow up our previous study, in which we have designed and characterized piperazine and piperidine triazole ureas as highly potent and MAGL-selective inhibitors culminating in the synthesis of JJKK-048, which appeared the most potent and MAGL selective inhibitor currently described (IC50 < 0.4 nM).20 Here, we describe the further optimization of piperazine and piperidine carboxamides and carbamates as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors.

Section snippets

Chemistry

(Benzhydrylpiperazin-1-yl)carboxamides 3af were synthesized by triphosgene-mediated coupling of benzhydrylpiperazine 1 with either with the appropriate aniline or heterocyclic amine (Scheme 1). Compounds 3gh were synthesized as shown in Scheme 1 starting by carbamylation of the heterocyclic amines with phenyl (4a) or p-nitrophenyl chloroformate (4b) to give the phenyl carbonyl derivatives 5ab. Subsequent urea formation of 5ab with 1 yielded 3gh.

The urea derivatives 7ae were obtained from

Benzhydryl-, phenyl- and ethoxycarbonylpiperazine derivatives

In the previous paper, we demonstrated that SAR629, the covalent inhibitor co-crystallized with MAGL14 and its close structural analog AKU-005, inhibited MAGL activity with subnanomolar potencies (IC50 values 0.2–1.1 nM).20 As the IC50 values towards FAAH were not reported in our previous paper, we present here inhibition results of human recombinant FAAH (hrFAAH) accompanied by MAGL inhibition data (Table 1). We demonstrated previously, that the replacement of the triazole moiety with p

Conclusion

In this paper, we have demonstrated that the triazole, benzotriazole, and triazolopyridine ureas show activity against MAGL (JJKK-048 and 12c) whereas the other leaving groups were significantly less active or inactive. As we concluded in our previous paper, triazole heterocycles are good leaving groups because their relatively low conjugate acid pKa values (8–10), that are optimal for the nucleophilic attack by the MAGL active site catalytic serine. On the other hand, the compounds having the p

General methods

1H and 13C NMR spectra were recorded on a Bruker Avance instrument operating at 500.1 and 25.8 MHz, respectively. Chemical shifts are reported as d values (ppm) relative to an internal standard of tetramethylsilane (TMS) or to the solvent line of DMSO (δH = 2.50 ppm quintet, δC = 39.43 ppm septet). The following abbreviations were used to explain multiplicities: b, broad; d, doublet; m, multiplet; q, quartet; s, singlet; sep, septet; sext, sextet; t, triplet. Electrospray ionization mass spectra were

Acknowledgements

This work was supported by the Academy of Finland (Grants 139620 to J.T.L. and 139140 J.T.N.) Biocenter Finland/DDCB (T.L.). The authors are grateful to Mrs. Tiina Koivunen for technical assistance. CSC–Scientific Computing, Ltd is greatly acknowledged for software licenses and computational resources.

References and notes (31)

  • C.J. Fowler et al.

    Biochem. Pharmacol.

    (2001)
  • M.P. Patricelli et al.

    Bioorg. Med. Chem. Lett.

    (1998)
  • S.G. Kinsey et al.

    J. Pain

    (2010)
  • M.N. Hill et al.

    Trends Pharmacol. Sci.

    (2009)
  • D.K. Nomura et al.

    Cell

    (2010)
  • K. Otrubova et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • T. Bertrand et al.

    J. Mol. Biol.

    (2010)
  • L. Morera et al.

    Bioorg. Med. Chem.

    (2012)
  • M. Kono et al.

    Bioorg. Med. Chem.

    (2013)
  • M. Kono et al.

    Bioorg. Med. Chem.

    (2014)
  • J.W. Hicks et al.

    Nucl. Med. Biol.

    (2014)
  • N. Aaltonen et al.

    Chem. Biol.

    (2013)
  • J. Chang et al.

    Chem. Biol.

    (2012)
  • D.J. Gustin et al.

    Bioorg. Med. Chem. Lett.

    (2011)
  • H. Käsnänen et al.

    Eur. J. Pharm. Sci.

    (2013)
  • Cited by (23)

    • Synthesis and hydrolysis of monocarbamate from allylic 1,4-dicarbamate: Bis-homodichloroinositol

      2022, Carbohydrate Research
      Citation Excerpt :

      Carbamate-bearing molecules form an important class of compounds that display various interesting properties [1,2]. While organic carbamates are used as intermediates in organic synthesis [2–8] in fields such as pharmaceuticals [9–13], agricultural chemicals [14,15] (pesticides, herbicides, insecticides, fungicides, etc.), they are used as intermediates in the protection of amino groups in peptide chemistry [16] and are also used as linkers in combinatorial chemistry [17,18]. Today, many drugs and/or prodrugs contain the carbamate moiety in their structure.

    • Synthesis and evaluation of dual fatty acid amide hydrolase-monoacylglycerol lipase inhibition and antinociceptive activities of 4-methylsulfonylaniline-derived semicarbazones

      2022, Bioorganic and Medicinal Chemistry
      Citation Excerpt :

      Based on the hydrolytic mechanism of FAAH/MAGL and their role in various nervous system disorders and neuro-inflammatory disease, several irreversible/reversible FAAH, MAGL, and dual FAAH-MAGL inhibitors have been investigated in past decades (Fig. 1). In the earlier phase of investigation piperazine and piperidine urea/carbamate compounds were considered as irreversible FAAH and MAGL inhibitor15. Compound JZL184 well characterized selective irreversible MAGL inhibitor used to treat various neurodegenerative disorders16 and bone cancer pain17.

    • Development of a highly-specific <sup>18</sup>F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping

      2021, Acta Pharmaceutica Sinica B
      Citation Excerpt :

      Inhibition of MAGL not only reduces the production of pro-inflammatory eicosanoids, but also increases 2-AG signaling, thereby providing a promising therapeutic direction for the treatment of the disorders mentioned above. As such, the development of MAGL inhibitors with high affinity and selectivity has caught considerable interest in the field of medicinal chemistry and drug discovery24–35. Complementary to routine clinical diagnostic application, positron emission tomography (PET) is a well-characterized noninvasive nuclear imaging tool, which has emerged to be invaluable for target engagement and phase 0 studies in the discovery of CNS drugs36–38.

    View all citing articles on Scopus
    View full text