Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists–serotonin reuptake transporter inhibitors for the treatment of depression
Graphical abstract
Introduction
Since their introduction in the 1980s, selective serotonin reuptake inhibitors (SSRIs) such as paroxetine,1 fluoxetine and citalopram (Chart 1) have enjoyed tremendous clinical and commercial success due to their improved safety profile over the first-generation tricyclic antidepressants like imipramine (Chart 1).2 Nevertheless, they still display several side effects including gastrointestinal distress, anxiety, insomnia, weight gain and sexual dysfunction. Like other currently approved antidepressants, SSRIs also suffer from slow onset of action, and as a result, a significant number of depressed patients do not show signs of mood improvement until 4–3 weeks after the initial treatment.3, 4, 5 The delay of therapeutic effects of SSRIs is believed to result from activation of the inhibitory role of serotonin 1A (5-HT1A) autoreceptors. Upon administration of an SSRI, some of the increased synaptic serotonin (5-HT) acting at 5-HT1A receptors reduces the firing of serotonergic neurons, resulting in a muted increase of synaptic 5-HT. After initial desensitization of the 5-HT1A autoreceptors with repeated SSRI treatment, the serotonergic neurons resume normal firing, allowing an increase of synaptic 5-HT, and thus generating a therapeutic antidepressant effect. Indeed, a beneficial effect on the onset of action of SSRIs has been observed in the clinical studies with co-administration of 5-HT1A antagonists.6, 7 Moreover, this combination therapy has resulted in significant improvements among SSRI-resistant patients.6, 7
Another potential combination strategy might involve neurokinin 1 receptor (NK1R) antagonists8, 9, 10, 11, 12 and SSRIs. NK1R antagonists alone may not be sufficient in treating depression in humans. For example, aprepitant, an NK1R antagonist currently used in combination with other antiemetics to help prevent the acute and delayed nausea and vomiting associated with emetogenic cancer chemotherapies, showed some antidepressant effect in early clinical studies,13 but its development for the treatment of depression was later discontinued after the compound’s effects failed to separate from placebo effects in phase III trials.14 Since NK1R antagonists indirectly modulate 5-HT function15, 16 and attenuate presynaptic 5-HT1A receptor function, NK1 receptor antagonism may augment the antidepressant activity of SSRIs. Consistent with this hypothesis, Bourin et al. demonstrated that GR205171 (Chart 1), a selective and brain penetrant NK1R antagonist, selectively potentiated the antidepressant activity of subactive doses of two SSRIs, citalopram and paroxetine, in the mouse forced swimming test (FST).17 Thus, combination therapy of SSRIs with NK1R antagonists has potential as a new treatment for depression with more rapid onset of action and improved efficacy. However, combination therapy with two compounds can have potential disadvantages, including challenges with differing PK profiles of the individual components, enhanced risk of drug–drug interactions, increased number or intensity of side effects, potentiation of dose-related or idiosyncratic side effects and pharmacokinetic interactions. An attractive alternative to combination therapy of two different molecules would be a single compound that has both serotonin reuptake transporter (SERT) inhibition and NK1R antagonism. In 2002, Ryckmans et al. described a series of benzyloxyphenethyl piperazine derivatives as dual NK1R antagonists-SERT inhibitors.18, 19 One of the best compounds in the series, (S)-1-(2-(3,5-dibromobenzyloxy)-1-phenylethyl)piperazine (1, Chart 1), demonstrated oral activity in an animal model of depression sensitive to both mechanisms.
We also undertook a program to identify dual NK1R antagonists-SERT inhibitors. We selected a known potent NK1R antagonist, 4-((3,5-bis(trifluoromethyl)-benzyloxy)-methyl)-4-phenylpiperidine (2, Chart 1),14 as one of the lead compounds for our medicinal chemistry program because of its structural similarity to known SSRIs such as paroxetine. We sought to add SERT inhibitory activity by judiciously incorporating key features of SSRIs into the molecule, while maintaining NK1R antagonism. It was in this context that we discovered that 2 was not only a potent NK1R antagonist but also a potent SERT inhibitor. This finding led to a series of 4,4-disubstituted piperidines and homopiperidines designed as potent dual NK1R antagonists-SERT inhibitors. This report details the synthesis, SAR and preliminary behavioral studies of these compounds.
Section snippets
Chemistry
The compounds in Table 1 were prepared as follows. Piperidines 2 and 3 were synthesized following the procedures described by Stevenson et al.20 Compound 4 was made from 2 via standard Boc protection. Analogues 5–7 were prepared as outlined in Scheme 1, Scheme 2.
Scheme 1 describes the synthesis of lactam 5 and piperidine 6 (Table 1). Double α-allylation of methyl 2-phenylacetate gave methyl 2-allyl-2-phenylpent-4-enoate 22. Ring closing metathesis of 22 proceeded smoothly with Grubbs I catalyst
Binding assays
The hNK1R binding affinity of the test compounds in this study was determined using U373 cells that express the human NK1 receptor. Non-specific binding was measured in the presence of certain concentrations of L-733,060, a non-peptide NK1 antagonist.12 The amount of radioligand bound in the presence and absence of L-733,060 was analyzed by plotting (−)log drug concentration versus the amount of radioligand specifically bound. The midpoint of the displacement curve (IC50, nM) signifies the
Results and discussion
Optimization of dual-acting molecules presents unique challenges in following SAR trends for two different targets. Based on our preliminary studies (data not shown), the 3,5-bis(trifluoromethyl)benzyl ether side chain appeared to be optimal for NK1 activity. Therefore, this side chain was fixed throughout this study. As summarized in Table 1, N-methylation of the piperidine nitrogen in compound 2 (cf. 3) had little impact on the NK1R activity, but the SERT activity was significantly
Further in vitro profile of compound 2
In parallel with our efforts to expand the SAR around compound 2, we elected to further profile this analog. Compound 2 was tested in a commercial screening package (PanLabs) and did not exhibit significant (<50% inhibition at 10 μM concentration) interactions with any of the over 70 other receptors except the following: NET, DAT, H1, H2, 5-HT2B, Na+ and Ca+2 channels). Follow-up in-house assays showed the IC50’s for the dopamine and norepinephrine transporters to be > 1 μM. Likewise, the IC50’s
Behavioral studies on 2
Species differences between the human NK1 receptor and NK1 receptors in rats and mice have resulted in many classes of NK1R antagonists having reduced affinity for rat and mouse NK1 receptors compared to human NK1 receptors. These species differences make it difficult to test for efficacy in traditional rat and mouse behavioral models. However, NK1R antagonists generally have similar affinity at gerbil and human NK1 receptors. In the case of compound 2, we found comparable potency for binding
Conclusion
Piperidine 2 and homopiperidine 8 were identified as potent dual NK1R antagonists and SERT inhibitors. Behavioral studies of 2 in the gerbil forced swimming test (FST) suggest that dual NK1R antagonists/SERT inhibitors may have potential for the treatment of depression disorders. Further SAR studies of this class of dual NK1R antagonists/SERT inhibitors will be reported in due course.
Preparation of membranes
Crude membrane suspensions were prepared for the NK1 and SERT radioligand binding assays from U373 cells or recombinant HEK-293 cells expressing hNK1 and hSERT, respectively. Cells were harvested from T-175 flasks as follows. The medium is removed from the flasks and the cells rinsed with HBSS without Ca and without Mg. The cells are then incubated for 5–10 min in 10 mM Tris-Cl, pH 7.5, 5 mM EDTA before the cells are lifted with a combination of pipetting and scraping, as needed. To prepare
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