e-52862 and Disease-Models--Animal

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4

Topics: Analgesics; Animals; Cell Membrane Permeability; Disease Models, Animal; Female; Half-Life; Humans; Ligands; Male; Mice; Microsomes, Liver; Pain; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship; Triazoles

Topics: Amides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Guinea Pigs; Injections, Subcutaneous; Mice; Mice, Inbred ICR; Molecular Structure; Neuralgia; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Receptors, sigma; Sciatic Nerve; Sigma-1 Receptor; Structure-Activity Relationship

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

By use of the 6-hydroxypyridazinone framework, a new series of potent σ1 receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ1 receptor affinity (Ki σ1 = 1.4 nM) and excellent selectivity over not only σ2 receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one (compound 54). Compound 54 exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound 54 was evaluated using phenytoin and indicated that the compound was a σ1 receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound 54 may be a member of a novel class of candidate drugs for treatment of neuropathic pain.

Topics: Analgesics, Non-Narcotic; Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Formaldehyde; Guinea Pigs; Ligands; Mice; Neuralgia; Pain Measurement; Pyridazines; Rats, Sprague-Dawley; Receptors, Opioid, delta; Rotarod Performance Test; Structure-Activity Relationship

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.

Topics: Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Injections, Intraperitoneal; Isoxazoles; Ligands; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship