Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides as TRPM8 antagonists.
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.
Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai 400 709, India.
Sachin S
SS
Chaudhari
Ashok B
AB
Kadam
Neelima
N
Khairatkar-Joshi
Indranil
I
Mukhopadhyay
Pallavi V
PV
Karnik
Anupindi
A
Raghuram
Shobha S
SS
Rao
Thamil Selvan
TS
Vaiyapuri
Dinesh P
DP
Wale
Vikram M
VM
Bhosale
Girish S
GS
Gudi
Ramchandra R
RR
Sangana
Abraham
A
Thomas
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D006207:Half-Life; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000700:Analgesics; D010880:Piperidines; D013141:Spiro Compounds; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; C032727:piperidine
Cold allodynia; Neuropathic pain; Optical resolution of alcohols; Spiro[chromene-2,4′-piperidines]; Wet-dog shake