2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure–activity relationships in the B and C-regions

On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure–activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region wa...

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Published in:Bioorganic & medicinal chemistry 2012-02, Vol.20 (3), p.1310-1318
Main Authors: Sun, Wei, Liu, Keliang, Ryu, HyungChul, Kang, Dong Wook, Kim, Yong Soo, Kim, Myeong Seop, Cho, Yongsung, Bhondwe, Rahul S., Thorat, Shivaji A., Kim, Ho Shin, Pearce, Larry V., Pavlyukovets, Vladimir A., Tran, Richard, Morgan, Matthew A., Lazar, Jozsef, Ryder, Christopher B., Toth, Attila, Blumberg, Peter M., Lee, Jeewoo
Format: Article
Language:English
Subjects:
Analgesic
Analgesics - chemistry
Analgesics - pharmacology
Animals
Biological and medical sciences
Capsaicin
CHO Cells
Cricetinae
Humans
Medical sciences
Mesylates - chemistry
Mesylates - pharmacology
Pharmacology. Drug treatments
Phenylpropionates - chemistry
Phenylpropionates - pharmacology
Rats
Resiniferatoxin
Structure-Activity Relationship
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - metabolism
TRPV1 antagonists
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Summary:On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure–activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with Ki=21.5nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with Ki(ant)=8.0nM comparable to 3.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.12.014