Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Abstract

A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with K=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.

Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift

“…The K i values for antagonism take into account the competition between capsaicin and the antagonist. 19 To evaluate the antagonistic potency of the compounds in Tables 2 and 3 for hTRPV1, assays were conducted using a fluorometric imaging plate reader (FLIPR) with hTRPV1 heterologously expressed in recombinant human embryonic kidney (HEK) cells. 15 The antagonistic activity was measured by inhibition of TRPV1 activation by capsaicin (10 nM) and was compared to that of the prototype antagonist, BCTC (K i(CAP) = 2.5 nM).…”

“…For the synthesis of 1-oxo-1,2-dihydroisoquinolin-5-yl Aregion analogues (Scheme 2), 1-chloroisoquinoline was hydrolyzed to the corresponding 2-pyridone and then nitrated to give 5-nitro isoquinolin-1-one 16. The nitro reduction or Nmethylation followed by reduction of 16 afforded 17 and 18, respectively, which were converted to the final ureas (3,19) by employing the same route as discussed above. For the synthesis of the 1-oxo-1,2-dihydroisoquinolin-8-yl A-region analogue (Scheme 2), isoquinoline was brominated and then selectively nitrated to give 8-nitro isoquinoline 21.…”

“…For the antagonism assay, the dose-dependent inhibition of the capsaicin (30 nM)-stimulated calcium uptake was measured. The K i values for antagonism take into account the competition between capsaicin and the antagonist …”

“…4.9.22. 1-(2-Methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)-3-((2-(4methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea(19). From 18, procedures G and F, yield 81% (in 2 steps), white solid, mp = 245.9−247.6 °C;1 H NMR (300 MHz, DMSO-d 6 ): δ 8.58 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.45 (m, 3H), 7.05 (m, 1H), 6.70 (d, J = 7.7 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2H), 3.50 (s, 3H), 2.78 (m, 2H), 1.72 (m, 2H), 1.29 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 161.1, 160.6, 155.5, 137.4, 134.4, 133.1, 130.9, 128.6, 126.3, 126.0, 123.3, 120.9, 113.8, 99.1, 50.0, 36.3, 33.8, 30.2, 21.8; HRMS (FAB): calcd for C 23 H 27 F 3 N 5 O 2 [M + H] + , 474.2039; found, 474.2115.4.9.23.…”

Serious Explosion during Large-Scale Preparation of an Amine by Alane (AlH3) Reduction of a Nitrile Bearing a CF3 Group

“…Much better results were achieved by reduction with the BH 3 *THF complex, but this reagent is expensive and can hardly be used in large-scale syntheses. LAH itself was used for the reduction of nonfluorinated pyrazolic nitriles to amines . We found that LAH reduction usually gave impure products with our substrates, and a laborious separation procedure was necessary.…”