SB-705498 / GSK - LARVOL DELTA

Inhibition of TRPV1 attenuates innate nasal epithelial responses via NF-κB signaling pathway in allergic rhinitis. (PubMed, Int Immunopharmacol) - "Allergen exposure enhances the secretion of IL-33 in hNECs via the TRPV1-NF-κB pathway, thus compromising epithelial tight junction integrity. Inhibition of TRPV1 can attenuate the effects of allergen-induced innate nasal epithelial responses. Our study offers novel insights into the potential therapeutic targeting of TRPV1 in AR."

Journal • Allergic Rhinitis • Allergy • Immune Modulation • Immunology • Inflammation • IL33 • OCLN • TRPV1

Three-Dimensional Quantitative Structure-Activity Relationship Study of Transient Receptor Potential Vanilloid 1 Channel Antagonists Reveals Potential for Drug Design Purposes. (PubMed, Int J Mol Sci) - "Starting from previously designed compounds, derived from the hybridization of antagonist SB-705498 and partial agonist MDR-652, we performed a virtual screening on a pharmacophore model built by exploiting the Cryo-EM 3D structure of a nanomolar antagonist in complex with the human TRPV1 channel. Again, we determined the compounds' binding poses after alignment to the pharmacophoric model, and we predicted their inhibition rates with the validated 3D-QSAR model. The obtained values resulted in being even more promising than parent compounds, demonstrating that ongoing research still leaves much room for improvement."

Journal • Pain

Polypeptide Nanoparticles Conjugated with an NIR-II Organic Dye for TRPV1 Channel Blockade Enhance Mild phototheranostics. (PubMed, Acta Biomater) - "Here, we successfully synthesized a fluorescent probe bonded with an amphiphilic polypeptide to a cyanine dye and achieved physical encapsulation of the blocker SB705498 through a self-assembly process...The nanoparticles also enable NIR-II fluorescence imaging with good stability and high photothermal conversion efficiency (48.10%). Thus, this study provides a new strategy for NIR-II mPTT."

Journal • Oncology • HSF1

A-80426 suppresses CFA-induced inflammatory pain by suppressing TRPV1 activity via NFκB and PI3K pathways in mice. (PubMed, Clinics (Sao Paulo)) - "Together, A8 exerted a narcotic impact on CFA-supplemented mice via the TRPV1-modulated NFκB and PI3K pathway."

Journal • Preclinical • Inflammation • Pain • IL1B • IL6 • NF-κβ • TNFA • TRPV1

Library Screening and Preliminary Characterization of Synthetic Cannabinoids Against Prostate and Pancreatic Cancer Cell Lines. (PubMed, Cannabis Cannabinoid Res) - "The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB antagonist, SR144528, but not modulated by the CB antagonist, rimonabant, and GPR55 antagonist, ML-193, nor TRPV antagonist, SB-705498...Combining each fluoro compound with an autophagy inhibitor, hydroxychloroquine, enhanced the apoptosis...Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D."

Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • GPR55

High Throughput Confined Migration Microfluidic Device for Drug Screening. (PubMed, Small) - "Three compounds that can significantly inhibit confined migration in pan-cancer: mitochonic acid 5 (MA-5), SB-705498, and diphenyleneiodonium chloride are found. Finally, it is elucidated that these drugs targeted mitochondria, actin polymerization, and cell viability, respectively. In sum, a high-throughput microfluidic platform for screening drugs targeting confined migration is established and three novel inhibitors of confined migration in multiple cancer types are identified."

Journal • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

DOPAMINE REGULATES AUTOPHAGY DURING TGF-Β1-INDUCED ACTIVATION OF HEPATIC STELLATE CELLS (UEGW 2022) - "Western-blot showed that DA and capsaicin could significantly reduce the expression of α - SMA, autophagy gene LC3 protein and autophagy flow in activated HSCs, which were eliminated by TRPV1 inhibitor sb-705498 or by interfering with the function of TRPV1... Dopamine may act as a protective factor in the process of liver fibrosis. Dopamine may activate TRPV1 calcium channel on cell membrane to mediate extracellular calcium influx, leading to intracellular calcium remodeling, and then inhibit the autophagy and activation of HSCs mediated by TGF-β1/Smad3 signaling pathway, and finally play an anti-fibrosis role."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • SMAD3 • TGFB1

Mechanosensitive Piezo2 Channel Mediates The Exaggerated Exercise Pressor Reflex In A Mouse Model Of Hind Limb Ischemia. (BCVS 2022) - "The exaggerated EPR was significantly reduced by intra-arterial administration of Gadolinium (a mechanical sensitive group III afferent neurons inhibitor), GsMTx-4 (a selective Piezo2 inhibitor), but not by SB-705498 (a TRPv1 receptor inhibitor)...Future studies will be aimed at interrogation of the mechanosensitive mechanisms that mediate this abnormal response to exercise in a model of PAD. The goal of these studies will be to determine molecular targets through which the exaggerated EPR can be normalized to allow for the prescription of exercise in PAD patients."

Preclinical • Cardiovascular • Peripheral Arterial Disease

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy. (PubMed, Eur J Pain) - "Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain."

Journal • Immunology • Pain • Peripheral Neuropathic Pain • TRPV1

Discovery of (S)-N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide as potent and brain-penetrant TRPV1 antagonist. (PubMed, Eur J Med Chem) - "In this work, in order to develop potent, CNS-penetrant, and orally available TRPV1 antagonists, three series of novel molecules based on the key pharmacophore structures of classic TRPV1 ligands SB-705498 and MDR-652 were designed and synthesized. Molecular docking and dynamics studies indicated that the high binding affinity of compound 7q to TRPV1 was related to multiple interactions, which resulted in significant conformational changes of TRPV1. Overall, our findings have led to a potent, mode-selective, and CNS-penetrant TRPV1 antagonist as a valuable lead for development of novel TRPV1 antagonists."

Journal • Pain

SGK1-targeted TRPV1 regulates bladder smooth muscle cell proliferation due to BOO in mice via NFAT2. (PubMed, IUBMB Life) - "In this study, SGK1 targeted TRPV1 to regulate the proliferation of MBSMCs mediated by BOO in mice through NFAT2 and then affected the process of bladder remodeling after BOO. This finding may provide a strategy for BOO drug target screening."

Journal • Preclinical • Benign Prostatic Hyperplasia • PCNA

[VIRTUAL] DOPAMINE REGULATES AUTOPHAGY DURING TGF-Β1-INDUCED ACTIVATION OF HEPATIC STELLATE CELLS (UEGW 2021) - "Western-blot showed that DA and capsaicin could significantly reduce the expression of α - SMA, autophagy gene LC3 protein and autophagy flow in activated HSCs, which were eliminated by TRPV1 inhibitor sb-705498 or by interfering with the function of TRPV1... Dopamine may act as a protective factor in the process of liver fibrosis. Dopamine may activate TRPV1 calcium channel on cell membrane to mediate extracellular calcium influx, leading to intracellular calcium remodeling, and then inhibit the autophagy and activation of HSCs mediated by TGF-β1/Smad3 signaling pathway, and finally play an anti-fibrosis role."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • SMAD3 • TGFB1

[VIRTUAL] DOPAMINE REGULATES AUTOPHAGY DURING TGF-Β1-INDUCED ACTIVATION OF HEPATIC STELLATE CELLS (UEGW 2021) - "Western-blot showed that DA and capsaicin could significantly reduce the expression of α - SMA, autophagy gene LC3 protein and autophagy flow in activated HSCs, which were eliminated by TRPV1 inhibitor sb-705498 or by interfering with the function of TRPV1... Dopamine may act as a protective factor in the process of liver fibrosis. Dopamine may activate TRPV1 calcium channel on cell membrane to mediate extracellular calcium influx, leading to intracellular calcium remodeling, and then inhibit the autophagy and activation of HSCs mediated by TGF-β1/Smad3 signaling pathway, and finally play an anti-fibrosis role."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • SMAD3 • TGFB1

[VIRTUAL] DOPAMINE REGULATES AUTOPHAGY DURING TGF-Β1-INDUCED ACTIVATION OF HEPATIC STELLATE CELLS (UEGW 2021) - "Western-blot showed that DA and capsaicin could significantly reduce the expression of α - SMA, autophagy gene LC3 protein and autophagy flow in activated HSCs, which were eliminated by TRPV1 inhibitor sb-705498 or by interfering with the function of TRPV1... Dopamine may act as a protective factor in the process of liver fibrosis. Dopamine may activate TRPV1 calcium channel on cell membrane to mediate extracellular calcium influx, leading to intracellular calcium remodeling, and then inhibit the autophagy and activation of HSCs mediated by TGF-β1/Smad3 signaling pathway, and finally play an anti-fibrosis role."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • SMAD3 • TGFB1

The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a Mouse Model of Dravet Syndrome. (PubMed, Front Pharmacol) - "However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a mice...These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS."

Journal • Preclinical • CNS Disorders

[VIRTUAL] Heterozygous deletion of Trpv1 reduces the severity but not the frequency of spontaneous seizures in a Scn1a+/- model of Dravet syndrome. (AES 2020) - "Additionally, we examined the effect of selective Trpv1 antagonist, SB-705498, on hyperthermia-induced seizures of Scn1a+/- mice... While antagonism of Trpv1 has anticonvulsant properties in several mouse seizure models, targeting Trpv1 either genetically or pharmacologically does not appear to be very effective in the Scn1a+/- mouse model of DS. Furthermore, heterozygous deletion of Trpv1 in Scn1a+/- mice was even pro-convulsant against febrile seizures at P18. Antagonism of Trpv1 appears not to be a versatile anticonvulsant target in the Scn1a+/− mouse model of DS."

CNS Disorders

Design, synthesis, and evaluation of isoquinoline ureas as TRPV1 antagonists. (PubMed, Med Chem) - "The para-substituted analogues were found to be more potent than the ortho- and meta- analogues in the biological assay. This observation was further supported by molecular modeling studies using CoMFA."

Journal • Musculoskeletal Pain • Pain

Improved Pharmacodynamic Profile of XEN-D0501, a Novel TRPV1 Antagonist, Over SB705498 Does Not Result in a Reduction in Cough Frequency in Patients with Chronic Idiopathic Cough (ATS 2017) - "XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin cough challenge studies compared to SB705498. This improved pharmacodynamic profile did not confer improvements in spontaneous coughing in patients with chronic cough. These studies demonstrate the superior profile of XEN-D0501 but suggest that TRPV1 is not an effective therapeutic target for patients with refractory cough."

HEOR • Biosimilar