[Translation] A randomized, double-blind, placebo-controlled, single- and multiple-dose ascending phase I clinical study to evaluate the safety, tolerability, and pharmacodynamics of WS012 in healthy Chinese adult subjects

主要目的：评估WS012在中国健康成人受试者中单次和多次口服给药的安全性和耐受性。次要目的：评估WS012在中国健康成人受试者中单次和多次口服给药的总胆汁酸（TBA）和粪便中TBA的药效动力学。探索性目的：探索健康受试者多次口服给药WS012对血脂（TG、TC、HDL-C、LDL-C）的影响。

[Translation]

Primary objective: To evaluate the safety and tolerability of WS012 after single and multiple oral administration in healthy Chinese adult subjects. Secondary objective: To evaluate the pharmacodynamics of total bile acid (TBA) and fecal TBA in WS012 after single and multiple oral administration in healthy Chinese adult subjects. Exploratory objective: To explore the effects of multiple oral administration of WS012 on blood lipids (TG, TC, HDL-C, LDL-C) in healthy subjects.

Start Date04 Jan 2024

Sponsor / Collaborator

Waterstone Pharmaceuticals (HuBei) Co., Ltd.

[+1]

100 Clinical Results associated with WS-012

100 Translational Medicine associated with WS-012

100 Patents (Medical) associated with WS-012

Literatures (Medical) associated with WS-012

01 Feb 2023·Journal of Applied Physiology

Irritant-evoked reflex tachyarrhythmia in spontaneously hypertensive rats is reduced by inhalation of TRPM8 agonists l-menthol and WS-12

Article

Author: Hooper, J. Shane ; Taylor-Clark, Thomas E.

Irritant-evoked pulmonary-cardiac reflexes are remodeled in spontaneously hypertensive (SH) rats—causing de novo sympathetic reflexes that drive tachyarrhythmia. This remodeling may contribute to air pollution-associated risk in susceptible individuals with cardiovascular disease. We found that inhalation of TRPM8 agonists, l-menthol and WS-12, but not the inactive analog d-menthol, selectively reduces the reflex tachyarrhythmia evoked by allyl isothiocyanate (AITC) inhalation in SH rats. Use of menthol may protect susceptible individuals from pollution-associated CV exacerbations.

01 Jan 2023·British Journal of Pharmacology

TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β‐catenin signalling

Article

Author: Cattaneo, Fabio ; Capasso, Raffaele ; Falco, Geppino ; Izzo, Angelo A. ; Zoppoli, Pietro ; Fiorucci, Stefano ; Nanì, Maria Francesca ; De Cicco, Paola ; D'Armiento, Maria ; Lucariello, Giuseppe ; Cicia, Donatella ; Marchianò, Silvia ; De Luca, Marcello ; Borrelli, Francesca ; Pagano, Ester ; Romano, Barbara ; Di Marzo, Vincenzo ; Lama, Stefania ; Venneri, Tommaso ; Stiuso, Paola ; Iannotti, Fabio A. ; Lionetti, Ruggiero

AbstractBackground and PurposeTransient receptor potential melastatin type‐8 (TRPM8) is a cold‐sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC).Experimental ApproachTRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8−/− mice in models of sporadic and colitis‐associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC.Key ResultsTRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt–Frizzled signalling hyperactivation and adenomatous polyposis coli down‐regulation. In sporadic and colitis‐associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β‐catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β‐catenin and its target oncogenes such as C‐Myc and Cyclin D1.Conclusion and ImplicationsHuman data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.

01 Nov 2021·ChiralityQ4 · CHEMISTRY

Ligand‐stereoselective allosteric activation of cold‐sensing TRPM8 channels by an H‐bonded homochiral menthol dimer with head‐to‐head or head‐to‐tail

Q4 · CHEMISTRY

Review

Author: Wang, Guangyu

AbstractBoth menthol and its analog WS‐12 share the same hydrophobic intra‐subunit binding pocket between a voltage‐sensor‐like domain and a TRP domain in a cold‐sensing TRPM8 channel. However, unlike WS‐12, menthol upregulates TRPM8 with a low efficacy but a high coefficient of a dose response at membrane hyperpolarization and with ligand stereoselectivity at membrane depolarization. The underlying mechanisms are unknown. Here, this in silico research suggested that the ligand‐stereoselective sequential cooperativity between two menthol molecules in the WS‐12 pocket is required for allosteric activation of TRPM8. Furthermore, two H‐bonded homochiral menthol dimers with both head‐to‐head and head‐to‐tail can compete for the WS‐12 site via non‐covalent interactions. Although both dimers can form an H‐bonding network with a voltage sensor S4 to disrupt a S3–S4 salt bridge in the voltage‐sensor‐like domain to release a “parking brake,” only one dimer may drive channel opening by pushing a “gas pedal” in the TRP domain away from the S6 gate against S4. In this way, the efficacy is decreased, but the cooperativity is increased for the menthol effect at membrane hyperpolarization. Therefore, this review may extend a new pathway for ligand‐stereoselective allosteric regulation of other voltage‐ and ligand‐gated ion channels by menthol.

100 Deals associated with WS-012

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Cholangitis, Sclerosing	Phase 1	CN	Waterstone Pharmaceuticals (Wuhan) Co., Ltd.	04 Jan 2024
Hyperlipidemias	Phase 1	-	Waterstone Pharmaceuticals (Wuhan) Co., Ltd.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

WS-012

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation