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Structure-activity relationship studies of four novel 4-aminopyridine K⁺ channel blockers.

ABSTRACT: 4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (K_V1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [¹⁸F]3F4AP, a radiofluorinated analog of 4AP, also binds to K_V1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH₃), methoxy (-OCH₃) as well as trifluoromethyl (-CF₃) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K⁺ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF₃4AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF₃4AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

SUBMITTER: Rodriguez-Rangel S

PROVIDER: S-EPMC6952366 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers.

Rodríguez-Rangel Sofia S Bravin Alyssa D AD Ramos-Torres Karla M KM Brugarolas Pedro P Sánchez-Rodríguez Jorge E JE

Scientific reports 20200109 1

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3</s ...[more]

PMID: 31919372

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Project description:Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.

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Structure-activity relationship studies of four novel 4-aminopyridine K⁺ channel blockers.

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Structure-activity relationship studies of four novel 4-aminopyridine K<sup>+</sup> channel blockers.

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Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers.

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Structure-activity relationship studies of four novel 4-aminopyridine K&lt;sup&gt;+&lt;/sup&gt; channel blockers.

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Structure-activity relationship studies of four novel 4-aminopyridine K⁺ channel blockers.

Structure-activity relationship studies of four novel 4-aminopyridine K<sup>+</sup> channel blockers.