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. (15th December 2022)

• Record Type: Journal Article
• Authors: Sabat, M.; Raveglia, L.F.; Aldegheri, L.; Barilli, A.; Bianchi, F.; Brault, L.; Brodbeck, D.; Feriani, A.; Lingard, I.; Miura, J.; Myers, R.; Piccoli, L.; Tassini, S.; Tyhonas, J.; Ton-Nu, T.; Wang, H.; Virginio, C.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 76(2022)
• Publication Date: 2022-12-15
• Subjects: TRPM5 -- Agonism -- Gastrointestinal -- Pro kinetic; ACh acetylcholine -- ADME absorption, distribution, metabolism and excretion -- ALS amyotrophic lateral sclerosis -- Cav1.2 calcium voltage-gated channel subunit 1.2 -- CHO Chinese hamster ovary cells -- CRC concentration response curve, CRO, contract research organization -- Cl clearance -- CNS central nervous system -- cryo-EM cryo-electron microscopy -- Da Daltons -- DMPK Drug metabolism and pharmacokinetics -- FLIPR fluorometric imaging plate reader -- FMP FLIPR membrane potential -- FPO fecal pellet output -- GI gastrointestinal -- HEK human embryonic kidney -- hERG human ether-a-go-go-related gene -- HLM human liver microsomes -- HTS high throughput screen -- IL-25 Interleukin 25 -- JP1 and JP2 Japanese Pharmacopoeia Dissolution Test Fluid No. 1 (pH 1.2), Japanese Pharmacopoeia Dissolution Test Fluid No. 2 (pH 6.8) -- LE ligand efficiency -- LLE lipophilic ligand efficiency -- LLC-PK1-MDR1 Lilly Laboratories Cell- Porcine Kidney-Madin-Darby canine kidney-1 -- MS multiple sclerosis -- Nav1.5 sodium voltage-gated channel subunit 1.5 -- NC neuropathic constipation -- PD Parkinson disease -- PD pharmacodynamic -- PK pharmacokinetic -- RLM rat liver microsomes -- SAR structure-activity relationship -- SCI spinal cord injury -- SD Sprague Dawley -- TPPO triphenylphosphine oxide -- TRPA transient receptor potential cation channel subfamily A -- TRPM transient receptor potential cation channel subfamily M -- TRPV transient receptor potential cation channel subfamily V -- Vd volume of distribution; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117084
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1 R, 3 R )-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1, 2, 3, 4-tetrahydroisoquinoline-6-carbonitrile (39 ). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.