7-Substituted-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as antagonists of the transient receptor potential ankyrin 1 (TRPA1) channel: a promising approach for treating pain and inflammation.
The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N(7)-phenylacetamide or N(7)-[4-(substituted-phenyl)-thiazol-2-yl]-acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC(50)=400nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain.
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17-19, Ferrara, Italy. baraldi@unife.it
Pier Giovanni
PG
Baraldi
Romeo
R
Romagnoli
Giulia
G
Saponaro
Mojgan
M
Aghazadeh Tabrizi
Stefania
S
Baraldi
Pamela
P
Pedretti
Camilla
C
Fusi
Romina
R
Nassini
Serena
S
Materazzi
Pierangelo
P
Geppetti
Delia
D
Preti
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015220:Calcium Channels; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat