t -Butyl Pyridine and Phenyl C-region Analogues of 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent TRPV1 Antagonists

Abstract A series of 2-substituted 6- t -butylpyridine and 4- t -butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for h TRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with K i  = 0.1 nM and compound 60 S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7 S in our h TRPV1 homology model indicated that the interactions between the A/B-regions of 7 S with Tyr511 and the interactions between the t -butyl and ethyl groups in the C-region of 7 S with the two hydrophobic binding pockets of h TRPV1 contributed to the high potency.