Discovery of Potent, Orally Available Vanilloid Receptor-1 Antagonists. Structure−Activity Relationship of N-Aryl Cinnamides

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).

A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a Novel and Selective Transient Receptor Potential Type V1 Receptor Antagonist, Blocks Channel Activation by Vanilloids, Heat, and Acid

“…For example, arginine-rich peptides have been reported as TRPV1 blockers with analgesic activities (Planells-Cases et al, 2000). Other TRPV1 antagonists have been described recently, including N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (Valenzano et al, 2003), JYL1421 and KJM429 (Wang et al, 2002), SB-366791 (Gunthorpe et al, 2004), thiourea (Toth et al, 2004), compound 41 (Swanson et al, 2005), AMG9810 (Doherty et al, 2005), and 5-iodo-resiniferatoxin (Wahl et al, 2001). The present studies were carried out to characterize a novel TRPV1 receptor antagonist A-425619 that was optimized from hits identified by high-throughput screening of chemical libraries .…”

[3H]A-778317 [1-((R)-5-tert-Butyl-indan-1-yl)-3-isoquinolin-5-yl-urea]: a Novel, Stereoselective, High-Affinity Antagonist Is a Useful Radioligand for the Human Transient Receptor Potential Vanilloid-1 (TRPV1) Receptor

“…However, CPZ exhibits weak potency at the rat and human ) TRPV1 receptors and is limited as a tool by its actions at other receptors besides TRPV1 (Docherty et al, 1997;Liu and Simon, 1997). More recently, a number of structurally novel nonvanilloid TRPV1 antagonists have been described , Jetter et al, 2004Gomtsyan et al, 2005, Rami et al, 2004, Doherty et al, 2005. A-425619 is one such compound that potently blocks TRPV1 receptor activation by capsaicin, acid, and heat Gomtsyan et al, 2005) and effectively reduces inflammatory pain in animal models .…”

“…These include the following: SB-452533 (Rami et al, 2004); AMG6880 (Doherty et al, 2005;Gavva et al, 2005); A-784168 (Cui et al, 2006); JNJ compound (Jetter et al, 2004);and A-425619 (El Kouhen et al, 2005) (Fig. 1).…”

Physiology and Pharmacology of the Vanilloid Receptor

“…Lastly, a group from Amgen has published a study on different analogs based on its acrylamide antagonist 38. From the N-aryl cinnamides synthesised, optimised compounds 39 and 40 exhibited high antagonist potency and good oral bioavailability in rats, as well as a favourable pharmacokinetic profile [33]. Although much of these compounds display in vivo anti-inflammatory and analgesic activity in animal models, further studies are required to assess the efficacy in the clinic.…”

“…(6). Novel TRPV1 antagonists lacking the urea or thiourea groups (31)(32)(33)(34)(35)(36), or based on the N-arylcinnamide moiety (37)(38)(39). identification of the pharmacophoric features required for orally active, potent antagonistic activity.…”