Novel Transient Receptor Potential Vanilloid 1 Receptor Antagonists for the Treatment of Pain:  Structure−Activity Relationships for Ureas with Quinoline, Isoquinoline, Quinazoline, Phthalazine, Quinoxaline, and Cinnoline Moieties

Abstract

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.

[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 .…”

“…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 . Further structure-activity studies of A-425619 led to the preparation of the (R)-and (S)-stereoisomers, A-778317 and A-778316.…”

Physiology and Pharmacology of the Vanilloid Receptor

“…In addition, two more derivatives, compounds 36 [14] and 37 [9], from Amgen containing heterocyclic moieties at the central regions have been also reported. More recently, the group of Abbott has described a collection of urea derivatives from which an analogue of compound 24 displaying a trifluoromethyl substituent at the meta position of the phenyl residue exhibited an IC 50 = 4 nM, a 46% of oral bioavailability and, in vivo analgesic activity in animal models of visceral and inflammatory pain [43]. Overall, the strength of the heterocyclic pharmacophores studied was 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline cinnoline phtalazine quinoxaline 5-quinoline.…”

First Examples of Doebner-Miller Reaction in Flow: Efficient Production of 2-Methylquinoline Derivatives in Water

“…Various conventional reactions such as Skraup reaction [1], Doebner-Miller reaction [2], Friedlander reaction [3], Pfitzinger reaction [4], Conrad-Limpach reaction [5], and Combes reaction [6] were reported depending on the substitution of the target compound. A large number of quinoline derivatives, 2-methylquinoline (quinaldine) for example, have showed significant biological activities, such as antimalarial [7], analgesic [8], anti-inflammatory [9], anticancer [10], antibacterial [11], and antifungal [12]. Quinoline derivatives are also used in cosmetics [13] and food colorants [14].…”