Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists
2013
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
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.
显示更多 [+] 显示较少 [-]