Delving into the Latest Updates on GRC-17536 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

TRPA1

Action

inhibitors

Mechanism

TRPA1 inhibitors(Transient receptor potential cation channel subfamily A member 1 inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Diabetic peripheral neuropathy

Inactive Indication

Peripheral Nerve InjuriesRefractory chronic cough

Originator Organization

Glenmark Pharmaceuticals Ltd.

Active Organization

IGI Therapeutics SA

Inactive Organization

Glenmark Pharmaceuticals Ltd.

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC20H13F5N4O3S2

InChIKeyXOPMVFNBFICPDB-UHFFFAOYSA-N

CAS Registry1246761-03-4

Author: Elves, Philip ; Coelho, Anne-Marie ; Walter, Daryl ; Mesch, Stefanie ; Hess, Stephen ; Zollner, Thomas M. ; Flanagan, Stuart ; Bothe, Ulrich ; Bäurle, Stefan ; Rotgeri, Andrea ; Basting, Daniel ; Pearson, Christopher ; Laux-Biehlmann, Alexis ; Steinmeyer, Andreas ; Jenkins, James ; Nawaz, Schanila ; Miyatake Ondozabal, Hideki

Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy. Consequently, there is an increasing interest in TRPA1 inhibitors as potential analgesics. Herein, we report the identification of a fragment-like hit from a high-throughput screening (HTS) campaign and subsequent optimization to provide a novel and brain-penetrant TRPA1 inhibitor (compound 18, BAY-390), which is now being made available to the research community as an open-source in vivo probe.

01 Sep 2020·Expert Opinion on Therapeutic PatentsQ2 · MEDICINE

Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015–2019)

Q2 · MEDICINE

Review

Author: Terrett, Jack A. ; Chen, Huifen

INTRODUCTIONTRPA1 is a non-selective cation channel predominantly expressed in sensory neurons, and functions as an irritant sensor for a plethora of noxious external stimuli and endogenous ligands. Due to its involvement in pain, itch, and respiratory syndromes, TRPA1 has been pursued as a promising drug target.AREAS COVEREDIn this review, the small molecule patent literature of TRPA1 antagonists from 2015-2019 was surveyed. The patent applications are described with a focus on chemical structures, biochemical/pharmacological activities, and potential clinical applications. The development of TRPA1 antagonists in clinical trials has been highlighted.EXPERT OPINIONDuring 2015-2019, significant progress was made toward the discovery of new TRPA1 antagonists. A total of 14 organizations published 28 patent applications disclosing several distinct classes of chemical matter and potential uses. During this period, three new molecules entered the clinic (ODM-108, HX-100, and GDC-0334) bringing the total number of TRPA1 antagonists to reach clinical trials to five (including earlier molecules CB-625 and GRC 17536); however, to our knowledge, development of all five molecules have been discontinued. Further clinical trials of recent TRPA1 antagonists with good pharmacokinetics would be needed to help understand TRPA1 involvement in human diseases and its potential as a therapeutic target.

01 Jan 2017·Progress in Medicinal Chemistry

Recent Progress in the Discovery and Development of TRPA1 Modulators

Review

Author: Skerratt, S

TRPA1 is a well-validated therapeutic target in areas of high unmet medical need that include pain and respiratory disorders. The human genetic rationale for TRPA1 as a pain target is provided by a study describing a rare gain-of-function mutation in TRPA1, causing familial episodic pain syndrome. There is a growing interest in the TRPA1 field, with many pharmaceutical companies reporting the discovery of TRPA1 chemical matter; however, GRC 17536 remains to date the only TRPA1 antagonist to have completed Phase IIa studies. A key issue in the progression of TRPA1 programmes is the identification of high-quality orally bioavailable molecules. Most published TRPA1 ligands are commonly not suitable for clinical progression due to low lipophilic efficiency and/or poor absorption, distribution, metabolism, excretion and pharmaceutical properties. The recent TRPA1 cryogenic electron microscopy structure from the Cheng and Julius labs determined the structure of full-length human TRPA1 at up to 4Å resolution in the presence of TRPA1 ligands. This ground-breaking science paves the way to enable structure-based drug design within the TRPA1 field.

100 Deals associated with GRC-17536

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic Neuropathies	Preclinical	United Kingdom	Glenmark Pharmaceuticals Ltd.	16 Mar 2012
Diabetic Neuropathies	Preclinical	Germany	Glenmark Pharmaceuticals Ltd.	16 Mar 2012
Peripheral Nerve Injuries	Preclinical	Germany	Glenmark Pharmaceuticals Ltd.	16 Mar 2012
Peripheral Nerve Injuries	Preclinical	United Kingdom	Glenmark Pharmaceuticals Ltd.	16 Mar 2012
Diabetic peripheral neuropathy	Discovery	Czechia	Glenmark Pharmaceuticals Ltd.	01 Nov 2012
Diabetic peripheral neuropathy	Discovery	United Kingdom	Glenmark Pharmaceuticals Ltd.	01 Nov 2012
Diabetic peripheral neuropathy	Discovery	India	Glenmark Pharmaceuticals Ltd.	01 Nov 2012
Diabetic peripheral neuropathy	Discovery	Germany	Glenmark Pharmaceuticals Ltd.	01 Nov 2012
Peripheral Nerve Injuries	Discovery	Germany	Glenmark Pharmaceuticals Ltd.	16 Mar 2012
Peripheral Nerve Injuries	Discovery	United Kingdom	Glenmark Pharmaceuticals Ltd.	16 Mar 2012