1245738-01-5Relevant articles and documents
Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro- 1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists
Chaudhari, Sachin S.,Kadam, Ashok B.,Khairatkar-Joshi, Neelima,Mukhopadhyay, Indranil,Karnik, Pallavi V.,Raghuram, Anupindi,Rao, Shobha S.,Vaiyapuri, Thamil Selvan,Wale, Dinesh P.,Bhosale, Vikram M.,Gudi, Girish S.,Sangana, Ramchandra R.,Thomas, Abraham
, p. 6542 - 6553 (2013/10/22)
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: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.