N-Isoquinolin-5-yl-N′-aralkyl-urea and -amide Antagonists of Human Vanilloid Receptor 1.
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.
- ChemInform 10/2004; 35(41). DOI:10.1002/chin.200441218
- Annual reports in medicinal chemistry 01/2005; 40:185-198. DOI:10.1016/S0065-7743(05)40012-3 · 1.19 Impact Factor
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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).Journal of Medicinal Chemistry 02/2005; 48(1):71-90. DOI:10.1021/jm049485i · 5.48 Impact Factor