E-52862 / Esteve, Mundipharma, Purdue - LARVOL DELTA

Development of 2,8-diazaspiro[4.5]decan-3-ones as novel sigma-1 receptor antagonists and evaluation of antihyperalgesic effects. (PubMed, Bioorg Chem) - "Analgesic efficacy, assessed through Von Frey and Hargreaves tests, demonstrated significant pain relief against both mechanical and thermal stimuli at a dose of 30 mg/kg, with effects comparable to those of E-52862. Our study indicates that compound 52 is a promising candidate for the treatment of hyperalgesia, exhibiting strong selectivity and efficacy as a σ1R antagonist."

Journal • Pain

Targeting Sigma-1 and Sigma-2 Receptors in Neuropathic Pain: Pharmacology, Ligand Development, and Translational Progress. (PubMed, Brain Sci) - "This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies."

Journal • Review • Inflammation • Neuralgia • Pain

E-52862-A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy. (PubMed, Eur J Pain) - "These proof-of-concept studies validate the mode of action of E-52862, a selective sigma-1 receptor antagonist. In CPSP, E-52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E-52862; high placebo response rates may have prevented differentiation between E-52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma-1 receptor antagonists for peripheral neuropathic pain."

Clinical • Journal • P2 data • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Genetic and Pharmacological Blockade of Sigma-1 Receptors Attenuates Inflammation-Associated Hypersensitivity during Acute Colitis in CD1 Mice. (PubMed, Biomedicines) - "The effects of the selective σR antagonists BD1063 and E-52862 were also assessed in WT animals...The selective modulation of sensory-related pathways within the colon and spinal cord might be part of the underlying mechanisms. These observations support the pharmacological use of σR antagonists for the treatment of intestinal inflammation-induced hypersensitivity."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Pain

Advances with the discovery and development of novel Sigma 1 receptor antagonists for the management of pain. (PubMed, Expert Opin Drug Discov) - "Focus is given to E-52862 and [F]FTC-146 (aka CM-304) as their clinical development has broken ground for S1R antagonists- with both being first-in-class ligands for treatment and diagnostic imaging, respectively. S1R antagonists represent a unique intracellular target for pain modulation, due to the receptor's chaperone activity in modulating various proteins in pain pathways. The research on S1R has grown exponentially in the last twenty years, and as more is understood about the basic science of the receptor, the drug development in this field will also flourish."

Journal • Review • Neuralgia • Pain

Pharmacokinetics and brain sigma 1 (σ1) receptor occupancy of MR309, a selective σ1 receptor antagonist. (PubMed, Br J Clin Pharmacol) - "MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications."

Journal • PK/PD data • Neuralgia • Pain • Peripheral Neuropathic Pain

The Esteve laboratory tests a new antiviral against Covid-19 in patients [Google translation] (Cinco Dias) - "The historic Catalan laboratory Esteve has begun a study with patients to test its own molecule as an antiviral against Covid-19. The company has launched a phase II clinical trial, in which the efficacy of the drug is tested with dozens of people, together with the Hospital del Mar in Barcelona and the Pompeu Fabra University. The compound tentatively named E-52862 will be tested in the early treatment of outpatients with mild symptoms of Covid-19 and with confirmed infection....They are expected to recruit 120 volunteers..."

Trial status • Infectious Disease • Novel Coronavirus Disease

Sigma-1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain. (PubMed, Br J Pharmacol) - "These findings show dual effects of σ1R antagonism alleviating both short- and long-lasting antinociception during chronic osteoarthritis pain and identify E-52862 as a promising pharmacological agent to treat chronic pain and elude opioid tolerance."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

The sigma-1 receptor antagonists, promising players in fighting neuropathic pain. (PubMed, Pharm Pat Anal) - "Moreover, E-52862 developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans."

Journal • Gene Therapies • Neuralgia • Pain

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval - A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity. (PubMed) - "The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal."

Journal • Biosimilar • Pain

Critical role of sigma-1 receptors in central neuropathic pain-related behaviours after mild spinal cord injury in mice. (PubMed, Sci Rep) - "Accordingly, treatment of WT mice with the σR antagonist MR309 (previously developed as E-52862; S1RA) after SCI exerted antinociceptive effects (i.e. reduced mechanical allodynia and thermal hyperalgesia). Attenuated nociceptive responses in σR KO were accompanied by reduced expression of TNF- α and IL-1β as well as decreased activation/phosphorylation of NR2B-NMDA receptors and ERK1/2. These findings suggest that σR may modulate central neuropathic pain and point to regulation of sensitization-related phenomena as a possible mechanism."

Journal • Preclinical

Modulation of the TRPA1 ion channel by sigma-1 receptor (Neuroscience 2019) - "...In the context of pain, pharmacological treatment of mice with the σ-1R antagonist, E-52862 (provided by ESTEVE PHARMACEUTICALS SA), produces antinociceptive effects, and has been shown to reduce the symptoms of neuropathic pain but the molecular mechanism is still unresolved...These results implicate TRPA1 channels in the anti-nociceptive effects of σ-1R antagonists. All experimental procedures were carried out according to Spanish Royal Decree 1201/2005 and the ECC directive 2010/63/EU."

May a sigma-1 antagonist improve neuropathic signs induced by cisplatin and vincristine in rats? (PubMed, Eur J Pain) - "σ1R antagonist, MR-309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects."

Journal • Preclinical

Blockade of the Sigma-1 Receptor Relieves Cognitive and Emotional Impairments Associated to Chronic Osteoarthritis Pain. (PubMed, Front Pharmacol) - "These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception."

Journal

Supraspinal and Peripheral, but Not Intrathecal, σR Blockade by S1RA Enhances Morphine Antinociception. (PubMed, Front Pharmacol) - "...S1RA (E-52862) is a selective σR antagonist widely used to study the role of σRs...Additionally, the peripherally restricted opioid agonist loperamide was devoid of antinociceptive effect but produced antinociception when combined with S1RA. Neurochemical studies revealed that noradrenaline levels in the dorsal horn of the spinal cord were not increased at doses exerting potentiation of the antinociceptive effect of the opioid. In conclusion, the site of action of σR for opioid modulation on acute thermal nociception is located at the peripheral and supraspinal levels, and the opioid-potentiating effect is independent of the spinal noradrenaline increase produced by S1RA."

Journal

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice. (PubMed, Front Pharmacol) - "The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development."

Journal • Preclinical