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: 2.42). 07/2004; 14(12):3053-6. DOI: 10.1016/j.bmcl.2004.04.038
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.
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ABSTRACT: Capsaicin (1), the active component of hot chili peppers, and related irritant compounds exert their pharmacological effect via activation of an excitatory ion channel expressed on nociceptors . The cellular target for 1 was cloned and characterized from a cDNA from rat sensory neurons in 1997 and named the VR1 receptor . Additional members of the family were subsequently cloned in several laboratories leading to multiple names for the same receptor. This prompted the adoption of the transient receptor potential (TRP) nomenclature whereby the VR1 receptor is now known as the TRPV1 receptor . This family of receptors consist of a large class of ion channels characterized by their permeability to monovalent cations and calcium ions, exhibiting a common structure made up of subunits with six membrane spanning domains [4,5]. The cloning of the rat receptor was quickly followed by the cloning of the human isoform  together with the characterization of TRPV1 "knockout" mice by two groups [7,8]. Knockout studies demonstrated that the receptor plays a key role as an integrator of noxious and chemical stimuli that produce pain. The receptor may be activated by heat, low pH, additional vanilloids, including the ultrapotent daphnane diterpenoid resiniferatoxin (RTX) (2), and a range of endogenous mediators encompassing products of the lipoxygenase pathway, bradykinin, and the endocannabinoid anandamide [1,9,10]. Thus numerous activators, often associated with tissue injury or inflammation, appear to operate by reducing the heat threshold of the receptor.
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ABSTRACT: The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).
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