Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM8

Title: Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides as TRPM8 antagonists.

Authors: Sachin S Chaudhari, Ashok B Kadam, Neelima Khairatkar-Joshi, Indranil Mukhopadhyay, Pallavi V Karnik, Anupindi Raghuram, Shobha S Rao, Thamil Selvan Vaiyapuri, Dinesh P Wale, Vikram M Bhosale, Girish S Gudi, Ramchandra R Sangana, Abraham Thomas

Journal, date & volume: Bioorg. Med. Chem., 2013 Nov 1 , 21, 6542-53

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24055075

Abstract
A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.