Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues oftrans-Cinnamides

Abstract

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.

Repeated Administration of Vanilloid Receptor TRPV1 Antagonists Attenuates Hyperthermia Elicited by TRPV1 Blockade

“…In our efforts to identify a TRPV1 antagonist clinical candidate, we synthesized several novel series of molecules representing various chemotypes ( Xi et al, 2005;Ognyanov et al, 2006;Norman et al, 2007;unpublished data) and evaluated their ability to block various modes of TRPV1 activation. AMG 517 inhibited capsaicin, pH 5, and heat-induced 45 Ca 2ϩ uptake into cells expressing TRPV1 with IC 50 values of 1 to 2 nM (Table 1, Fig.…”

“…After evaluation of TRPV1 antagonists representing various chemotypes Xi et al, 2005;Ognyanov et al, 2006;Norman et al, 2007;unpublished data) for potency, selectivity, plasma half-life, effects in the capsaicin-induced flinch model, and efficacy in models of inflammatory pain, we identified AMG 517 as a potential drug for the management of pain in humans. Here, we describe the characterization of AMG 517 and the data set leading to its selection as a clinical candidate.…”

Investigation of nucleophilic substitution pathway for the reactions of 1,4-benzodioxan-6-amine with chlorocyclophosphazenes

“…In the present work, the reactions of tetramer and trimer with 1,4-benzodioxan-6-amine used in pharmaceutical applications such as antagonists [35], cytotoxic molecules for inhibitory activity against human breast cancer cells [36] were investigated in order to determine their nucleophilic substitutions pathway and compare to cyclotri-and tetraphosphazenes.…”

A Study of Anti-inflammatory and Analgesic Activity of New 2,4,6-Trisubstituted Pyrimidines

“…15) Literature revealed that the some substituted pyrimidines act as novel and potent TRPV1 antagonists for the treatment of hyperalgesia. 16,17) In view of these references, the synthesis of a new series of 2,4,6-trisubstituted pyrimidines are now reported. The desired target compounds (5a-m) were prepared from the 1,3-diarylpropenones (3a-m) 18,19) and guanidine (4) by refluxing them together in a basic alcoholic media (Chart 1).…”