Heterocycle-linked Phenylbenzyl Amides as Novel TRPV1 Antagonists and Their TRPV1 Binding Modes: Constraint-Induced Enhancement of In Vitro and In Vivo Activities

A series of heterocycle‐linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding mo...

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Bibliographic Details
Published in:Chemistry, an Asian journal an Asian journal, 2013-02, Vol.8 (2), p.400-409
Main Authors: Kim, Nam-Jung, Li, Fu-Nan, Lee, Jin Hee, Park, Seul-gi, Kim, Kyeojin, Lim, Changjin, Han, Young Taek, Yun, Hwayoung, Jung, Jong-Wha, Park, Hyeung-geun, Kim, Hee-Doo, Woo, Byoung Young, Shin, Song Seok, Kim, Sun-Young, Choi, Jin Kyu, Jeong, Yeon-Su, Park, Yanghui, Park, Young-Ho, Kim, Dae-Duk, Choi, Sun, Suh, Young-Ger
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacokinetics
Amides - therapeutic use
Analgesics
Analgesics - chemical synthesis
Analgesics - pharmacokinetics
Analgesics - therapeutic use
Animals
antagonists
Binding Sites
Chemistry
Furans - chemistry
Half-Life
Heterocyclic Compounds - chemistry
Hyperalgesia - chemically induced
Hyperalgesia - drug therapy
ligand design
Male
medicinal chemistry
Molecular Docking Simulation
molecular modeling
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - biosynthesis
Recombinant Proteins - genetics
Thiourea - chemistry
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - genetics
TRPV Cation Channels - metabolism
TRVP1
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Summary:A series of heterocycle‐linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan‐linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model. Flexibility not desired: A series of heterocycle‐linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan‐linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model.
ISSN:1861-4728
1861-471X
DOI:10.1002/asia.201200730