7-Hydroxynaphthalen-1-yl-urea and -amide antagonists of human vanilloid receptor 1

Design of Potent, Orally Available Antagonists of the Transient Receptor Potential Vanilloid 1. Structure−Activity Relationships of 2-Piperazin-1-yl-1H-benzimidazoles

“…During the past few years, several classes of TRPV1 antagonists, either structurally related or not to the exogenous agonists capsaicin and RTX, have been described, and their chemistry and pharmacology have been reviewed. − One extensively studied class of TRPV1 antagonists is based on urea templates. ,,− For example, the potent TRPV1 antagonist N -(4- tert -butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) ( 4 ) (Figure ) is a member of a well-studied chemical series of urea-based TRPV1 antagonists that contains a piperazine-1-carboxamide template. The BCTC template was disclosed for the first time by Neurogen and more recently by Johnson & Johnson, Bayer, GlaxoSmithKline, Abbott, and Purdue Pharma .…”

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.…”

“…To date, thousands of chemical compounds are reported in the literature as competitive TRPV1 antagonists, and some of them undergo clinical trials [5,16]. The majority of the compounds have been identified through high-throughput screening experiments [13–15,17]. Some of these compounds were further optimized by isosteric replacements of structural fragments [18–20] and by structure–activity relationship (SAR) studies [9–11,21–30].…”

Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

“…Additionally, these compounds were successfully converted into antagonists by modifying the thiomorpholino group in the amide moiety, based on a previous report in which the intrinsic efficacy at TRPV1 was shown to be especially sensitive to structural changes in the amide region. 17 These findings indicated that the 5,5-diarylpentadienamide is a suitable lead structure for the development of novel TRPV1 antagonists. On the basis of these leads, we started a research effort to improve the antagonistic activity, as well as increase metabolic stability, of these compounds.…”