N‐Isoquinolin‐5‐yl‐N′‐aralkyl‐urea and ‐amide Antagonists of Human Vanilloid Receptor 1.

Abstract

A series of title compounds of type (I), (II) and (III) is prepared as potent antagonists of human vanilloid receptor 1 (VR1). The structure-activity relationships of the series are discussed. -(JETTER, M. C.; YOUNGMAN, M. A.; MCNALLY, J. J.; ZHANG, S.-P.; DUBIN, A. E.; NASSER, N.; DAX*, S. L.; Bioorg.

Identification and Biological Evaluation of 4-(3-Trifluoromethylpyridin-2-yl)piperazine-1-carboxylic Acid (5-Trifluoromethylpyridin-2-yl)amide, a High Affinity TRPV1 (VR1) Vanilloid Receptor Antagonist

“…Modulation of TRPV1 activity was assessed in vitro by measuring compound-or capsaicin-induced Ca 2+ flux using FLIPR and HEK293 cells stably expressing recombinant human and rat TRPV1 (hTRPV1-HEK293 and rTRPV1-HEK293, respectively) as previously described. 21,13,22 Intracellular Ca 2+ levels were measured in TRPV1-expressing cells during exposure to compounds. A concentration dependent increase in Ca 2+ influx was observed using both human and rat cell lines for 19, 30, 31, 37, and 38 (Table 1).…”

“…FLIPR protocols and analysis were as described previously. , Briefly, hTRPV1-HEK293 and rTRPV1-HEK293 were seeded at ∼50 K cells/well in 96-well poly- d -lysine-coated BD plates, incubated overnight, and then loaded with 4 μM calcium fluorescent dye Fluo-3/AM (acetoxymethylester) (Teflabs, Austin, TX) with Pluronic-F127 (Sigma, St. Louis, MO; 0.01%) at room temperature for 60 min. Prior to testing on the FLIPR (Molecular Devices, Sunnyvale, CA), extracellular dye was aspirated and cells were incubated in assay buffer (containing in mM: NaCl 128, KCl 2, MgCl 2 1, dextrose 10, HEPES 20, CaCl 2 2; pH 7.45).…”

“…When the pyridine point of attachment was examined, 17 and 18, it was immediately apparent that the pyridin-2-ylpiperazine was optimal. A range of modifications to or replacements for the piperazine (20)(21)(22)(23)(24)(25)(26) showed that the piperazine ring was tolerant of small substituents (e.g. 20) but further substitution (21)(22)(23), ring expansion (24) or replacement with 3-aminopyrrolidine (25) or 4-aminopiperidine (26) afforded considerably less active compounds.…”

“…A range of modifications to or replacements for the piperazine (20)(21)(22)(23)(24)(25)(26) showed that the piperazine ring was tolerant of small substituents (e.g. 20) but further substitution (21)(22)(23), ring expansion (24) or replacement with 3-aminopyrrolidine (25) or 4-aminopiperidine (26) afforded considerably less active compounds. Removal of a single piperazine nitrogen (27 and 28), using the chemistry of Scheme 2, afforded a less active compound as did removal of both a piperazine and the pyridine nitrogens, using the chemistry of Scheme 3 (29 and 30).…”

Novel Transient Receptor Potential Vanilloid 1 Receptor Antagonists for the Treatment of Pain: Structure−Activity Relationships for Ureas with Quinoline, Isoquinoline, Quinazoline, Phthalazine, Quinoxaline, and Cinnoline Moieties

“…The organic layers were combined, dried over MgSO4, and evaporated under vacuum to give 2.23 g of desired product 26, which was used without further purification. 1 5-Amino-quinoxaline (27). A mixture of 5-nitro-quinoxaline (26) prepared above and 10% Pd/C (223 mg) in EtOH (100 mL) was hydrogenated at 60 psi for 1 h. The catalyst was removed by filtration, the filtrate was evaporated under vacuum, and the residue was chromatographed on silica gel (EtOAc/hexane, 1:1) to give 27 (0.45 g, 31% for two steps).…”