Article

N-isoquinolin-5-yl-N'-aralkyl-urea and -amide antagonists of human vanilloid receptor 1.

Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 07/2004; 14(12):3053-6. DOI: 10.1016/j.bmcl.2004.04.038
Source: PubMed

ABSTRACT Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.

0 Bookmarks
 · 
69 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: In peripheral sensory neurons, the vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) functions as a molecular integrator of painful stimuli, including those mediated by capsaicin, acid, and heat. Antagonist blockade of TRPV1 activation is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. TRPV1 is also expressed, albeit at lower levels, in the brain and in non-neuronal tissues, where its function(s) remains elusive. The contribution of TRPV1 receptor activity to physiological reflexes and disease states is complex and is only beginning to be understood. Consequently, the resultant effects of TRPV1 antagonists on the body may be unforeseen. Indeed, clinical trials with a number of TRPV1 antagonists were recently terminated due to their marked hyperthermic activity. In this review article, the medicinal chemistry of TRPV1 antagonists is discussed inasmuch as it relates to the efficacy, safety, tolerability and potential side effects of these compounds. In addition, the available information on the current status of the clinical trials with TRPV1 antagonists is summarized. Drug Dev Res 68:477–497, 2007. © 2008 Wiley-Liss, Inc.
    Drug Development Research 02/2008; 68(8):477 - 497. · 0.87 Impact Factor
  • Annual Reports in Medicinal Chemistry - ANNU REP MED CHEM. 01/2005; 40:185-198.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Publicly open databases of small compounds have become an indispensable tool for chemoinformaticians for collection and preparation of datasets suitable for drug discovery questions. Since these databases comprise compounds coming from structure-activity relationship (SAR) studies performed by different research groups, they are very diverse with respect to the biological assays used. In the present study we analyzed the applicability of a thoroughly curated dataset gathered from open sources for ligand-based studies, using the transient receptor potential vanilloid type 1 (TRPV1) as use case. Thorough curation of compounds according to the biological assay type and conditions led to a dataset of comparable bioactive chemicals. Subsequent exhaustive analysis of the obtained dataset using classification algorithms demonstrated that the models obtained in most of the cases possess reliable quality. Analysis of constantly misclassified compounds showed that they belong to local SAR series, where small changes in structure lead to different class labels. These small structural differences could not be captured by the classification algorithms. However application of the 3D alignment-independent QSAR technique GRIND for local, structurally related series overcomes this problem.
    Molecular Informatics 06/2013; 32(5-6):555-562. · 2.01 Impact Factor