NC-2600 / Nippon Chemiphar - LARVOL DELTA

Targeting P2X receptors for analgesia: Small molecule antagonists in development. (PubMed, Eur J Med Chem) - "For instance, Sivopixant is a highly selective P2X3R antagonist that exhibits potent analgesic efficacy in the rat spinal nerve ligation (SNL) model (ED50 = 0.4 mg/kg p.o.) and possesses favorable pharmacokinetic properties. And NC-2600, as a potent and specific P2X4R antagonist, demonstrated significant analgesic efficacy in a rat model of colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) at oral doses of 10 and 30 mg/kg...Additionally, A-740003 (49) is a potent, selective P2X7R antagonist that demonstrates broad-spectrum analgesic activity in both neuropathic and inflammatory pain models. These findings underline the potential of rational drug design to develop subtype-selective P2XR antagonists as novel analgesics for pain management."

Journal • Review • Addiction (Opioid and Alcohol) • Gastroenterology • Gastrointestinal Disorder • Immunology • Neuralgia • Pain

Targeting P2X receptor signaling for chronic visceral pain and beyond. (PubMed, Neuropharmacology) - "The first-generation P2X3/P2X7 antagonists (e.g., AF-219, AZD-9056, NC-2600) failed in clinical trials, primarily due to species-specific receptor pharmacology, the lack of ATP-based biomarkers for patient stratification, and irreversible central sensitization driven by epigenetic marks. To overcome these hurdles, we propose a precision-medicine framework that includes: (1) CRISPR-dCas9-based epigenome editing as a potential one-time "pain-memory eraser"; (2) patient stratification using sweat-ATP levels; and (3) human iPSC-derived neuron screening to improve translational predictability. This integrated approach holds promise not only for CVP related to irritable bowel syndrome (IBS), but also for other pain conditions."

Journal • Review • Gastrointestinal Disorder • Pain

Pharmacological inhibition of P2RX4 receptor as a potential therapeutic strategy to prevent intracranial aneurysm formation. (PubMed, Exp Neurol) - "Consistently, the selective P2RX4 antagonist NC-2600, which potently inhibited Ca2+ influx in response to shear-stress loading in endothelial cells in vitro, significantly suppressed the formation of IAs. The results of the present study contribute to our understanding of the pathogenesis of IAs and may provide benefits to society through the future development of medical therapies targeting P2RX4."

Journal • Cardiovascular • Giant Cell Arteritis • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • P2RX4

P2X4 receptor mediates macrophage infiltration leading to endometriotic cyst epithelium proliferation and hyperalgesia in mouse model. (PubMed, F S Sci) - "These results indicate unknown pathophysiological roles of P2X4R expressed in local macrophages at the injury site of endometriosis and in the vagina, suggesting the potential therapeutic effects of orally administered P2X4R inhibitors for alleviating the symptoms of endometriosis."

Journal • Preclinical • Endometriosis • Gynecology • Pain • Women's Health

The pharmacological blockade of P2X4 receptor as a viable approach to manage visceral pain in a rat model of colitis. (PubMed, J Drug Target) - "Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction...By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1β axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1β axis inhibition."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Pain • IL1B • NLRP3 • OCLN

ANTI-INFLAMMATORY EFFECTS OF NOVEL P2X4 RECEPTOR ANTAGONISTS, NC-2600 AND NP-1815-PX, IN A MURINE MODEL OF COLITIS (DDW 2022) - "Methods : Test drugs [NC-2600, NP-1815-PX and dexamethasone (DEX)] were administered orally for 6 days, immediately after the delivery of DNBS. This effect was inhibited upon incubation with NC-2600 and NP-1815-PX. Conclusion s: These findings demonstrated for the first time that the direct and selective inhibition of P2X4 receptors represent a viable approach for the management of bowel inflammation via the inhibition of the canonical and non-canonical NLRP3 inflammasome signaling pathways."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • CASP8 • IL1B • NLRP3 • TNFA

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis. (PubMed, Inflammation) - "These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1β release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • CASP8 • IL1B • NLRP3 • TNFA

[VIRTUAL] Nippon Chemiphar (BIO 2021) - "Although several P2X3R antagonists have been developed, we believe P2X4R is ideal target for chronic cough and NC-2600 will be effective for wider range of chronic cough than targeting P2X3. Its Ph-1 is completed in Japan, and no taste disturbances were observed, which is one of concerns of P2X3R antagonists."

Pulmonary Disease • Respiratory Diseases

Nociceptive signaling of P2X receptors in chronic pain states. (PubMed, Purinergic Signal) - "The phase I study of NC-2600 has been completed, and no serious side effects were reported. The roles played by purinergic receptors in evoking neuropathic pain provide crucial insights into the pathogenesis of neuropathic pain."

Journal • Review • Immunology • Neuralgia • Pain • Peripheral Neuropathic Pain