2‑(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure–Activity Relationships of 2‑Amino Derivatives in the N‑(6-Trifluoromethylpyridin-3-ylmethyl) C‑Region

A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino...

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Published in:Journal of medicinal chemistry 2012-10, Vol.55 (19), p.8392-8408
Main Authors: Kim, Myeong Seop, Ryu, HyungChul, Kang, Dong Wook, Cho, Seong-Hee, Seo, Sejin, Park, Young Soo, Kim, Mi-Yeon, Kwak, Eun Joo, Kim, Yong Soo, Bhondwe, Rahul S, Kim, Ho Shin, Park, Seul-gi, Son, Karam, Choi, Sun, DeAndrea-Lazarus, Ian A, Pearce, Larry V, Blumberg, Peter M, Frank, Robert, Bahrenberg, Gregor, Stockhausen, Hannelore, Kögel, Babette Y, Schiene, Klaus, Christoph, Thomas, Lee, Jeewoo
Format: Article
Language:English
Subjects:
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Body Temperature - drug effects
Capsaicin - pharmacology
CHO Cells
Cricetinae
Cricetulus
Dopamine - analogs & derivatives
Dopamine - pharmacology
Hot Temperature
Humans
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Docking Simulation
Neuralgia - drug therapy
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - genetics
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Summary:A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49 S was an excellent TRPV1 antagonist (K i(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49 S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49 S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49 S made additional hydrophobic interactions with the hydrophobic region.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300780p