RQ-00203078

Description:

IC50: 8.3 and 5.8 nM for hTRPM8 and rTRPM8, respectively

The transient receptor potential melastatin 8 (TRPM8), a member of the TRP melastatin sub-group, is known to play a role in cold hyperalgesia and cold allodynia caused by disease conditions such as chemotherapy-induced peripheral neuropathy (CIPN, using the agents oxaliplatin, vincristine, or paclitaxel), diabetic neuropathy, migraine and overactive bladder (OAB). RQ-00203078 is identified as a selective and orally active TRPM8 antagonist.

In vitro: In the menthol-induced calcium influx assay, RQ-00203078 is a novel and highly potent TRPM8 antagonist with human and rat IC50 values of 8.3 nM and 5.8 nM, respectively. RQ-00203078 was highly selective over other TRP channels [1].

In vivo: RQ-00203078 demonstrated excellent activity in vivo in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration [1].

Clinical trial: Up to now, RQ-00203078 is still in the preclinical development stage.

Reference:
[1] Ohmi M, Shishido Y, Inoue T, Ando K, Fujiuchi A, Yamada A, Watanabe S, Kawamura K.  Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist. Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8.

Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist.[Pubmed:25455182]

Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8.

A novel series of 2-pyridyl-benzensulfonamide derivatives have been identified as selective and orally active TRPM8 antagonists via high throughput screening (HTS). Exploration of the structure-activity relationships of compound 1 has led to the identification of RQ-00203078 (compound 36) as a highly selective, potent and orally available TRPM8 antagonist. RQ-00203078 demonstrated excellent in vivo activity in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration and may become an important pharmacological tool for fully assessing the potential therapeutic use of the targets activated by cold stimulation.

Blockade of TRPM8 activity reduces the invasion potential of oral squamous carcinoma cell lines.[Pubmed:22267123]

Int J Oncol. 2012 May;40(5):1431-40.

Several members of the transient receptor potential (TRP)-channel family are expressed in cancer cells. One, cold/menthol-sensitive TRPM8, is reportedly an important player in carcinogenesis in human prostate cancer, although its involvement in oral squamous cell carcinoma (SCC) remains unclear. The present immunohistochemistry and RT-PCR results revealed intense TRPM8 expression in two SCC cell lines, HSC3 and HSC4, derived from the human tongue. Menthol, icilin, and a more specific TRPM8 agonist (WS-12) induced non-specific cation currents, with Ca2+ permeability being greater than that of Na+ or K+. The novel TRPM8 antagonist RQ-00203078 (RQ) profoundly reduced such agonist-induced cation currents. Intracellular Ca2+ imaging revealed that menthol induced both intracellular Ca2+ release and store-operated Ca2+ entry, with RQ inhibiting each effect. To assess the possible pathophysiological role of TRPM8 in oral SCC, we performed motility and invasion assays, and gelatin zymography. Menthol augmented the migration and invasion abilities of both HSC3 and HSC4 cells by potentiating MMP-9 activity. RQ suppressed all of these effects. These results may aid understanding of the pathophysiological implications of TRPM8 channels in the oral SCC cells, support TRP proteins as valuable targets for pharmaceutical intervention, and inform the targeting of oral SCC in which the prognosis is poor.

RQ-00203078 is a highly selective, potent and orally available TRPM8 antagonist (IC50 values are 5.3 and 8.3 nM for rat and human channels respectively), exhibits >350-fold selectivity for TRPM8 over TRPV4, TRPV1 and TRPA1.

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