Synthesis and biological evaluation of novel dimiracetam derivatives useful for the treatment of neuropathic pain
Introduction
Neuropathic pain (NeP) is defined as chronic, persistent pain mostly caused by peripheral or central neural injury.1 Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. The characteristic symptoms of neuropathic pain are usually expressed as allodynia, hyperalgesia and spontaneous pain. The majority of the currently available treatments for NeP are not adequate: tricyclic antidepressants, anticonvulsants and opioids are only partially effective and/or are associated with significant side effects.2 Even gabapentin, the gold standard for the treatment of NeP, reduces pain by 30–50% at best in less than 50% of patients.3 Therefore, safer and more effective treatments for neuropathic pain need to be developed and significant efforts must be applied to the discovery of novel drug molecules able to alleviate this intractable pain.
Nootropic drugs comprise a series of derivatives of γ-aminobutyric acid (GABA) whose prototype, piracetam, is used in diseases characterized by learning and memory deficits (Fig. 1).4 Recent studies have shown that some nootropic drugs such as nefiracetam or levetiracetam may be useful in treating neuropathic pain both in animals and in patients.
The validation of nootropic pyrrolidinones in neuropathic pain is noteworthy. For example, nefiracetam, a Piracetam derivative, featuring a lipophilic anilide moiety, dose dependently reversed the thermal or mechanical hyperalgesia induced by partial sciatic nerve ligation or streptozotocin treatment in mice.5 Levetiracetam, an anticonvulsant drug targeting the synaptic vesicle protein SV2A, was recently shown to be effective in patients with chronic neuropathic pain, particularly when treatment with other anticonvulsant agents failed.6
The analgesic action induced by this class of derivatives was non-opioid in nature, as it was not reversed by the opioid antagonist naloxone. Together, these findings suggest that nefiracetam, and other cognition enhancers of the same pyrrolidinone nootropic class, could be good therapeutic tools against neuropathic pain, having no liabilities due to possible involvement of the opioid system, and an exceptional safety profile.7
Thus, taking nefiracetam as the model drug, we continued the research in this field with the aim of finding compounds endowed with increased potency, efficacy and with a good safety profile. Dimiracetam,8 a bicyclic pyrrolidinone analogue of piracetam, was developed as a novel cognition enhancer until Phase I, before its development was discontinued. This compound, which maintains the backbone of piracetam with the acetamide side chain restricted in a folded conformation, was 10–100 times more potent than piracetam and, as for the other related derivatives, practically devoid of toxicity.
In the present study, a series of variously substituted dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones 2–38, derivatives of 1, were prepared and their antihyperalgesic effect was investigated in several models of neuropathic pain in rats.
Section snippets
Chemistry
Substituted aromatic rings were inserted into the dimiracetam structure through a microwave-enhanced Goldberg reaction, allowing the synthesis of a small set of 37 compounds (Scheme 1).9
Microwave irradiation greatly accelerates this copper-catalysed arylation of the secondary amide. Compounds 2–38 (Table 1) were quickly obtained by irradiation of a mixture of dimiracetam and the corresponding aryl iodides or bromides, using NMP as solvent, in the presence of CuI as catalyst, in a microwave
Pharmacology
The lack of a well-known mechanism of action for racetam derivatives prevents primary in vitro screening and the selection of active compounds generally relies on in vivo testing. All the compounds prepared were tested on the Bennett and Xie12 model of neuropathic pain after i.c.v. injection. This route of administration was preferred to obtain a ‘pure’ measurement of efficacy, avoiding the influence of other parameters that could prevent an active compound from being detected (e.g., poor
Conclusion
Microwave assisted Goldberg reaction allowed rapid insertion of substituted phenyl rings onto a dimiracetam scaffold. Compounds 5, 7 and 8 dose dependently reverted mechanical hyperalgesia in sciatic nerve-ligated rats and streptozotocin-treated animals after i.c.v. and oral administration without inducing any motor impairment. Interestingly the action of these compounds is neuropathy-specific since no significant activity is detected on the unlesioned contralateral paw in mononeuropathic and
Chemistry
Reagents obtained from commercial sources were used without further purification. In order to monitor the progress of the reaction, thin layer chromatography (TLC) was performed using Merck silica gel 60 F254 precoated plates. Flash chromatography was performed using Merck silica gel 60, 230–400 mesh. The reported yields are unoptimized. Melting points were determined on a Buchi melting point B545 apparatus and are uncorrected. 1H NMR spectra were recorded on a Bruker AC 300. Mass spectra were
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