[A-425619, a Novel TRPV1 Receptor Antagonist -- Abbott]
>>J Pharmacol Exp Ther. 2005 Apr 18; [Epub ahead of print]
A-425619, a Novel TRPV1 Receptor Antagonist, Relieves Pathophysiological Pain Associated with Inflammation and Tissue Injury in Rats.
Honore P, Wismer CT, Mikusa JP, Zhu CZ, Zhong C, Gauvin DM, Gomtsyan A, El Kouhen R, Lee CH, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF.
Abbott Laboratories.
The vanilloid receptor 1 (VR1, TRPV1) which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine (NADA). A-425619 is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose-dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 micromol/kg, p.o.). A-425619 was also effective in models of inflammatory pain and post-operative pain. A-425619 potently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration (ED50 = 40 micromol/kg, p.o.) and was also effective after either intrathecal administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the post-operative pain model after twice daily dosing p.o. for five days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg, p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and post-operative pain.<<
So we've got Renovis/Pfizer, Amgen, and now Abbott with competing VR1 programs. Looks like a horse race, with entrants just out of the gate.
Edit: J&J is here, too. And, of course, Neurogen/Merck, where I meant to post this.
>>J Med Chem. 2005 Mar 24;48(6):1857-72.
Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist.
Swanson DM, Dubin AE, Shah C, Nasser N, Chang L, Dax SL, Jetter M, Breitenbucher JG, Liu C, Mazur C, Lord B, Gonzales L, Hoey K, Rizzolio M, Bogenstaetter M, Codd EE, Lee DH, Zhang SP, Chaplan SR, Carruthers NI.
Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.<<
Cheers, Tuck |
