Heteroaryl β-tetralin ureas as novel antagonists of human TRPV1

High-Throughput Screening of TRPV1 Ligands in the Light of the Bioluminescence Resonance Energy Transfer Technique

“…In the cluster F, Sertraline (#51), a 1,2,3,4tetrahydronaphtalen derivative, which is substituted by a methylamino at position 1 and a 3,4dichlorophenyl at position 4 (the S, S diastereoisomer), has been detected as an inhibitor by the BRET intramolecular probe and APC at +100 mV and -100 mV. Interestingly tetraline urea derivatives have been shown to display antagonistic properties against TRPV1 activation by CAPS (Messeguer et al, 2006;Jetter et al, 2007). While Sertraline is not a tetraline urea derivative, it would be interesting to assess whether substitution of the methylamino group of Sertraline by an urea group improve Sertraline potency and/or efficacy to inhibit CAPS-mediated TRPV1 activation.…”

Novel Scaffolds for Modulation of TRPV1 Identified with Pharmacophore Modeling and Virtual Screening

“…Cluster 2 comprised 63 substituted isoquinolin-aralkyl-ureas and -amides [15], hydroxynaphtalen-ureas and -amides [17] and heteroaryl β-tetralin ureas [23] with IC 50 values ranging from 2 to 100 nM. A potent clinical candidate, ABT-116 (IC 50 7 nM) [51], with an indazole-urea scaffold, was also present in this cluster.…”

Design, Synthesis and Biological Evaluation of 1,4-Disubstituted-3,4-dihydroisoquinoline Compounds as New Tubulin Polymerization Inhibitors

“…The general method used for the synthesis of the 3,4-dihydroisoquinoline derivatives was outlined in Scheme 1 . The condensation of 3 with aromatic aldehyde gave 4a–d , which were subsequently treated with NaBH 4 to afford amines 6a–d in good yield via independent two-step reduction reaction [ 9 , 10 ], then 6a–d was reacted with the substituted benzoic acids to give the substituted benzamides 7 – 19 . The target compounds 20 – 32 were finally obtained by Bischler-Napieralski cyclization of the corresponding benzamides 7 – 19 .…”