The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent
This publication details the discovery of a series of selective agonists for Transient Receptor Potential Melastatin 5 (TRPM5) culminating with the identification of a lead compound.
Gastrointestinal (GI) disease including inflammatory bowel disease (ulcerative colitis and Crohn’s disease), and GI motility disorders (neuropathic constipation (NC), and gastroparesis) are serious life limiting conditions for patients. TRPM5 is a non-selective monovalent cation channel activated by intracellular Ca2+ increase which, within the GI system, plays a critical role of propagating the signal through membrane depolarization and initiating the release of Interleukin (IL)-25 and other paracrine factors. We hypothesized that a TRPM5 agonist will activate the release of IL-25 and non-neuronal ACh, leading to improvement in motility through a prokinetic mechanism.
In the paper we describe:
- The process of our discovery starting from a high throughput screening hit through to the identification of a lead compound
- The selectivity of the lead compound versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8
- The drug metabolism and pharmacokinetics (DMPK) profile of the lead compound
- The in vivo efficacy of lead compound in a mouse model of gastrointestinal motility