Valentina Zuliani

Sodium channel blockers for neuropathic pain

Importance of the field: The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity, chronic and neuropathic pain. In particular, neuropathic pain (e.g., postherpetic and trigeminal neuralgia, diabetic neuropathy and spinal cord injury) is a serious clinical problem that affects a high percentage of the world population. Because an altered sodium channel isoform expression profile has been considered one reason for the changes in neuronal excitability, there is a continuous quest for new selective molecules targeting sodium channels for the treatment of chronic pain. Areas covered in this review: PubMed, http://www.sciencedirect.com/, SciFinder® Scholar and http://ep.espacenet.com/ were used as sources for this review and patents between 2007 and September 2009 were taken into account for the sodium channel blockers molecular classes reviewed and discussed herein. What the reader will gain: The sodium channel blockers reported in this review have been categorized into different molecular classes on the basis of their wide structural diversity. This classification, somewhat arbitrary, does not necessarily reflect the presence of pharmacophoric elements but offers a useful way to discuss and comment on structurally homogenous classes of chemotypes recently patented. Take home message: The continuous discoveries in the field of sodium channel blockers, highlighted by the increasing numbers of patent applications published in the last few years and by the numbers of compounds currently in clinical development, underline the importance of this target for the treatment of neuropathic pain. The great difficulty in the design of new selective and active structures, not obtained from old VGSC blockers that are often associated with high risk of adverse effects, is a strong challenge for medicinal chemistry research.

Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines

In this study, we examined the mechanism of action of the novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor 5-benzylidene-hydantoin UPR1024, whose structure was designed to interact at the ATP-binding site of EGFR. The compound had antiproliferative and proapoptotic effects when tested on the non–small cell lung cancer cell line A549. The growth inhibitory effect was associated with an accumulation of the cells in the S phase of the cell cycle. Moreover, UPR1024 induced significant level of DNA strand breaks associated with increased expression of p53 and p21WAF1 proteins, suggesting an additive mechanism of action. The presence of wild-type p53 improved the drug efficacy, although the effect was also detectable in p53 null cells. We also noted apoptotic cell death after treatment with UPR1024 at concentrations above 10 μmol/L for >24 h, with involvement of both the extrinsic and intrinsic pathways. The present data show that UPR1024 may be considered a combi-molecule capable of both blocking EGFR tyrosine kinase activity and inducing genomic DNA damage. UPR1024 or its derivatives might serve as a basis for development of drugs for the treatment of lung cancer in patients resistant to classic tyrosine kinase inhibitors. [Mol Cancer Ther 2008;7(2):361–70]

Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential

The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability. Abnormal activity of sodium channels is related to several pathological processes, including cardiac arrhythmias, epilepsy, chronic pain, neurodegenerative diseases and spasticity. In view of this, VGSCs are considered important therapeutic targets for the treatment of these disorders. To date, nine VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSCs also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective antagonists, but also antagonists that exhibit state selectivity, particularly to the inactivated state of the channel. This review will provide a brief historical prospective and will primarily focus on recent advances in the development of isoform specific and state selective sodium channel antagonists and the medicinal chemistry involved, surveying the emerging therapeutic fields.

5-Benzylidene-hydantoins: synthesis and antiproliferative activity on A549 lung cancer cell line.

Benzylidene hydantoins have been recently reported as a new class of EGFR inhibitors. We describe here a simple and efficient methodology for the parallel solution-phase synthesis of a library of 5-benzylidene hydantoins, which were evaluated for antiproliferative activity on the human lung adenocarcinoma A549 cell line. Various substituents at positions 1, 3 and 5 on the hydantoin nucleus were examined. In the presence of a 5-benzylidene group and of a lipophilic substituent at position 1, most of the tested compounds inhibited cell proliferation at a concentration of 20 microM. Compound 7 (UPR1024), bearing 1-phenethyl and (E)-5-p-OH-benzylidene substituents, was found to be the most active derivative of the series. It inhibited EGFR autophosphorylation and induced DNA damage in A549 cells. Compound 7 and other synthesized 5-benzylidene hydantoin derivatives increased p53 levels, suggesting that the dual mechanism of action was a common feature shared by compound 7 and other member of the series.

Microwave Assisted Efficient Synthesis of Imidazole-Based Privileged Structures

A simple and efficient microwave assisted synthesis of imidazobenzoxazines, imidazobenzoxazin-5-ones, and imidazobenzoxazin-5-thiones with broad chemistry scope is described. The molecules were prepared both under conventional as well as microwave heating conditions, to provide in high yields with clean and scalable reactions a small library of imidazole-based privileged structures for drug discovery.

Sodium Channel Blockers as Therapeutic Target for Treating Epilepsy: Recent Updates

The voltage-gated sodium channels (VGSCs) are a family of membrane proteins forming a pore, through which they selectively conduct sodium ions inward and outward cells plasma membranes in response to variations of membrane potentials, playing a fundamental role in controlling cellular excitability. Growing evidences suggest that abnormal VGSCs are involved in the pathophysiology of both acquired and inherited epilepsy. Approximately two dozen drugs are currently marketed for the treatment of epilepsy and most of them act as sodium channel blockers, preventing the return of the channels to the active state by stabilizing the inactive form. Despite the many drugs on the market, 30% of patients continue to experience seizures even in the presence of optimal doses of AEDs, while others continue to suffer from medication induced side effects. Thus, there is a great need to continue the search for new AEDs that are not only more effective, but also have a better side effects profile. For this reason, many efforts have been made in the recent years to identify new sodium channel blockers for the treatment of epilepsy. These studies have led to different classes of compounds, characterized by a great structural diversity. The aim of this review is to provide an introduction on the structure and function of the sodium channels, followed by a brief historical perspective on the sodium channel blockers in use as anticonvulsant drugs. Moreover, it will focus on the medicinal chemistry of the sodium channel blockers recently published (2008-2011) and the drug design/molecular modeling studies related to the receptor.

Novel sodium channel antagonists in the treatment of neuropathic pain

ABSTRACT Introduction: Effective and safe drugs for the treatment of neuropathic pain are still an unmet clinical need. Neuropathic pain, caused by a lesion or disease that affects the somatosensory system, is a debilitating and hampering condition that has a great economic cost and, above all, a tremendous impact on the quality of life. Sodium channels are one of the major players in generating and propagating action potentials. They represent an appealing target for researchers involved in the development of new and safer drugs useful in the treatment of neuropathic pain. The actual goal for researchers is to target sodium channels selectively to stop the abnormal signaling that characterizes neuropathic pain while leaving normal somatosensory functions intact. Areas covered: This review covers the most recent publications regarding sodium channel blockers and their development as new treatments for neuropathic pain. The main areas discussed are the natural sources of new blockers, such as venom extracts and the recent efforts from many pharmaceutical companies in the field. Expert opinion: There have been serious efforts by both the pharmaceutical industry and academia to develop new and safer therapeutic options for neuropathic pain. A number of different strategies have been undertaken; the main efforts directed towards the identification of selective blockers starting from both natural products or screening chemical libraries. At this time, researchers have identified and characterized selective compounds against NaV1.7 or NaV1.8 voltage-gated sodium channels but only time will tell if they reach the market.

2,4(5)-Diarylimidazoles as inhibitors of hNaV1.2 sodium channels: Pharmacological evaluation and structure–property relationships

Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)s values that were greater than 100 microM.

2,4(5)-Diarylimidazoles : Synthesis and biological evaluation of a new class of sodium channel blockers against hNav1.2

A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNa(v)1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Na(v)1.2 currents, emerging as a promising lead compound for further structure-activity relationship studies for the development of novel sodium channel blockers.

Inhibition of NaV1.6 sodium channel currents by a novel series of 1,4-disubstituted-triazole derivatives obtained via copper-catalyzed click chemistry

We have synthesized and evaluated a series of 1,4-disubstituted-triazole derivatives for inhibition of the rat Na(V)1.6 sodium channel isoform, an isoform thought to play an important role in controlling neuronal firing. Starting from a series of 2,4(1H)-diarylimidazoles previously published, we decided to extend the SAR study by replacing the imidazole with a different heterocyclic scaffold and by varying the aryl substituents on the central aromatic ring. The 1,4-disubstituted 1,2,3-triazoles were prepared employing the copper-catalyzed azide-alkyne cycloaddition (CuAAC). Many of the new molecules were able to block the rNa(v)1.6 currents at 10 μM by over 20%, displaying IC(50) values ranging in the low micromolar, thus indicating that triazole can efficiently replace the central heterocyclic core. Moreover, the introduction of a long chain at C4 of the central triazole seems beneficial for increased rNa(v)1.6 current block, whereas the length of N1 substituent seems less crucial for inhibition, as long as a phenyl ring is not direcly connected to the triazole. These results provide additional information on the structural features necessary for block of the voltage-gated sodium channels. These new data will be exploited in the preparation of new compounds and could result in potentially useful AEDs.