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Expert Opinion on Therapeutic Patents Volume 18, 2008 - Issue 2
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Review

Advances in the design and therapeutic use of capsaicin receptor TRPV1 agonists and antagonists

Laxmikant A Gharat Discovery Chemistry, Glenmark Pharmaceuticals, Navi Mumbai, India
, PhD &
Arpad Szallasi Departments of Pathology, Monmouth Medical Center, Long Branch, NJ, USA +1 732 923 7360; [email protected]; Drexel University College of Medicine, Philadelphia, PA, USA
, MD PhD
Pages 159-209 | Published online: 22 Feb 2008

Bibliography

  • Wood JN (ed.). Capsaicin in the Study of Pain. New York: Academic Press; 1993
  • Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 1999;51:159-212
  • Malmberg AB, Bley KR (eds). Turning up the Heat on Pain: TRPV1 Receptors in Pain and Inflammation. Basel: Birkhauser; 2005
  • Caterina M, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;380:816-24
  • Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007;6:357-72
  • Levine JD, Alessandri-Haber N. TRP channels: targets for the relief of pain. Biochim Biophys Acta 2007;1772:879-84
  • Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000;288:306-13
  • Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000;405:183-7
  • Christophs T, Grunweller A, Mika J, et al. Silencing of avnilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo. Biophys Biochem Res Commun 2006;350:238-43
  • Pingle SC, Matta JA, Ahern GP. Capsaicin receptor TRPV1: a promiscuous TRP channel. Handbook Exp Pharmacol 2007;179:153-69
  • Buck SH, Burks TF. The neuropharmacology of capsaicin. A review of some recent observations. Pharmacol Rev 1986;38:179-226
  • Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991;43:143-201
  • Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 1988;24:739-68
  • Rashid MH, Bakoshi S, Ueda H, et al. Novel expression of vanilloid receptor 1 on capsaicin-insensitive fibers accounts for the analgesic effect of capsaicin creams in neuropathic pain. J Pharmacol Exp Ther 2003;304:940-8
  • Rashid MH, Inoue M, Bakoshi S, Ueda H. Increased expression of vanilloid receptor 1 on myelinated primary afferent neurons contributes to the antihyperalgesic effect of capsaicin cream in diabetic neuropathic pain in mice. J Pharmacol Exp Ther 2003;306:709-17
  • Geppetti P, Holzer P (eds). Neurogenic Inflammation. Boca Raton: CRC Press; 1996
  • Szallasi A, Di Marzo V. New perspectives on enigmatic vanilloid receptors. Trends Neurosci 2000;23:491-7
  • Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol 2002;118:110-21
  • Gunthorpe MJ, Szallasi A. Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms. Curr Pharm Des 2008; in press
  • Suri A, Szallasi A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol Sci 2007; Epub ahead of print
  • Razavi R, Chan Y, Afifiyan FN, et al. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 2006;127:1123-35
  • Yiangou Y, Facer, Dyer NH, et al. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 2001;357:1338-9
  • Chan CL, Facer P, Davis JB, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and fecal urgency. Lancet 2003;361:385-91
  • Tympanidis P, Casula MA, Yiangou Y, et al. Increased vanilloid receptor VR1 innervation of vulvodynia. Eur J Pain 2004;8:129-33
  • Yilmaz Z, Renton Y, Yiangou Y, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: increased heat and capsaicin receptor TRPV1 expression correlates with pain score. J Clin Neurosci 2007;14:864-71
  • Matthews PJ, Aziz Q, Facer P, et al. Increased capsaicin receptor TRPV1 nerve fibers in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004;16:897-902
  • Facer P, Casula MA, Smith GD, et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol 2007;7:11-3
  • Gopinath P, Wan E, Holdcroft A, et al. Increased capsaicin receptor TRPV1 in skin nerve fibers and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain. BMC Womens Health 2005;5:2-6
  • Immke DC, Gavva NR. The TRPV1 receptor and nociception. Semin Cell Dev Biol 2006;17:582-91
  • Westaway SM. The potential of transient receptor potential vanilloid subfamily member 1 channel modulators for the treatment of pain. J Med Chem 2007;50:2589-96
  • McCleskey EW. Neuroscience: a local route to pain relief. Nature 2007;449:545-6
  • Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 agonist) therapy for pain relief: farewell or revival? Clin J Pain 2008;24(2):142-154
  • Winston Lab, Inc. WO2005037158 (2001)
  • Neurogesx, Inc. WO2004091521 (2004)
  • Algorx Pharmaceuticals, Inc. WO2006058140 (2006)
  • Remadevi R, Szallasi A. Drug evaluation: Adlea™ (ALGRX-4975), and injectable capsaicin (TRPV1 receptor agonist) formulation for long-lasting pain relief. Curr Opin Investig Drugs. In press 2008
  • Szallasi A, Fowler CJ. After a decade of intravesical vanilloid therapy, still more questions than answers. Lancet Neurol 2002;1:167-72
  • Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, functions, and clinical applications. Naunyn Schmiedebergs Arch Pharmacol 2006;373:287-99
  • Giannantoni A, Di Stasi SM, Chancelor MB, et al. New frontiers in intravesical therapy and drug delivery. Eur Urol 2006;50:1183-93
  • Sellers DJ, McKay N. Developments in the pharmacotherapy of the overactive bladder. Curr Opin Urol 2007;17:223-30
  • Sterner O, Szallasi A. Novel natural vanilloid receptor agonists: new therapeutic targets for drug development. Trends Pharmacol Sci 1999;20:459-65
  • Walpole CJ, Wrigglesworth R, Bevan S, et al. Analogues of capsaicin as novel analgesic agents: structure-activity studies. Part 1. The aromatic ‘A’ region. J Med Chem 1993;36:2362-72
  • Walpole CJ, Wrigglesworth R, Bevan S, et al. Analogues of capsaicin as novel analgesic agents: structure-activity studies. Part 2. The amide-bond ‘B’ region. J Med Chem 1993;36:2373-80
  • Walpole CJ, Wrigglesworth R, Bevan S, et al. Analogues of capsaicin as novel analgesic agents: structure-activity studies. Part 3. The hydrophobic side-chain ‘A’ region. J Med Chem 1993;36:2362-72
  • Walpole CJ, Bevan S, Bloomfield G, et al. Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues. J Med Chem 1996;39:2939-52
  • Urban L, Campbell EA, Panesar M, et al. In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue. Pain 2000;89:65-74
  • Wrigglesworth R, Walpole CJ, Bevan S, et al. Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. Part 4. Potent, orally active analgesics. J Med Chem 1996;39:4942-51
  • Szallasi A. Perspectives on vanilloids in clinical practice. Drug News Perspect 1997;10:522-7
  • Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S. VR1 receptor modulators as potential drugs for neuropathic pain. Mini Rev Med Chem 2003;3:729-48
  • Walpole CJ, Bevan S, Bovermann G, et al. The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. J Med Chem 1994;37:1942-54
  • McIntyre P, McLatchie LM, Chambers A, et al. Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 2001;132:1084-97
  • Gavva NR, Klionsky L, Qu Y, et al. Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 2004;279:20283-95
  • Corell CC, Phleps PT, Anthes JC, et al. Cloning and pharmacological characterization of mouse TRPV1. Neurosci Lett 2004;370:55-60
  • Walker KM, Urban L, Medhurst SJ, et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;304:56-62
  • Wahl P, Foged C, Tullin S, Thomsen C. Iodo-resiniferatoxin, a new potent vanilloid receptor antagonist. Mol Pharmacol 2001;59:9-15
  • Appendino G, Harrison S, De Petrocellis L, et al. Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists. Br J Pharmacol 2003;139:1417-24
  • Appendino G, De Petrocellis L, Trevisani M, et al. Development of the first ultra-potent “capsaicinoid” agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential. J Pharmacol Exp Ther 2005;312:561-70
  • McDonnell ME, Zhang SP, Dubin AE, Dax SL. Synthesis and invitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanniloid receptor. Bioorg Med Chem Lett 2002;12:1189-92
  • Appendino G, Daddario N, Minassi A, et al. The taming of capsaicin by reversal of the vanilloid activity of N-acylvanillamines by aromatic iodination. J Med Chem 2005;48:4663-9
  • Appendino G, Ech-Chahad A, Minassi A, et al. Structure-activity relationships of the ultrapotent vanilloid resiniferatoxin (RTX): the homovanillyl moiety. Bioorg Med Chem Lett 2007;17:132-5
  • Wang Y, Szabo T, Welter JD, et al. High affinity antagonists of the vanilloid receptor. Mol Pharmacol 2002;62:947-56
  • Lee J, Kang M, Blumberg PM, et al. N-(3-acyloxy-2-benzylpropyl)- N′-[4-(methylsulfonylamino) benzyl] thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor. J Med Chem 2003;46:3116-26
  • Kang DW, Ryu H, Lee J, et al. Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin. Bioorg Med Chem Lett 2007;17:214-9
  • Jakab B, Helyes Z, Varga A, et al. Pharmacological characterization of the TRPV1 antagonist JYL1421 (SC0030) in vitro and in vivo in the rat. Eur J Pharmacol 2005;517:35-44
  • AmorePacific Corp. WO2006098554 (2006)
  • Pharmeste S.r.l. WO2006045498 (2006)
  • Pharmeste S.r.l. WO2005123666 (2005)
  • Bakthavathcalam R. Capsaicin receptor ligands. WO0208221 (2002)
  • Dax SL, Dubin AE, Jetter M. Drugs Future 2002;27(Suppl A):93
  • Bayer Healthcare AG. JP2003192673 (2003)
  • Rami HK, Thompson M, MacDonald GJ, et al. Vanilloid Receptor Modulators. WO03068749 (2003)
  • Lee CH, Bayburt EK, Didomenico S, et al. Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1(VR1) receptor. WO03070247 (2003)
  • Tafesse L, Sun Q, Schmiedt L, et al. Synthesis and evaluation of pyridazinylpiperazines as vanilloid receptor 1 antagonists. Bioorg Med Chem Lett 2004;14:5513-9
  • Carruthers NI, Shah CR, Swanson DM. Preparation of pyridyl piperazinyl ureas with VR1 antagonistic activity.WO2005014580 (2005)
  • Sun Q, Tafesse L, Iislam K, et al. 4-(2-pyridyl)piperazine-1-carboxamides: potent vanilloid receptor 1 antagonists. Bioorg Med Chem Lett 2003;13:3611-6
  • Pomonis JD, Harrison JE, Lilly M, et al. (4-Tertiarybutylphenyl)-4- (3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II. In vivo characterization in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;306:387-93
  • Valenzano KJ, Grant ER, Wu G, et al. N-(4-tertiarybutylphenyl)-4- (3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I in vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther 2003;306:377-86
  • Roden DM, Lazarra R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 1996;94:1996-2012
  • Swanson DM, Dubin AE, Shah C, et al. Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethyl pyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor. J Med Chem 2005;48:1857-72
  • Amgen, Inc. WO2004035549 (2004)
  • Ognyanov VI, Balan C, Bannon AW, et al. Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles. J Med Chem 2006;49:3719-42
  • Neurogen Corp. WO2005084368 (2005)
  • Neurogen Corp. WO2004056774 (2004)
  • Merck Sharp & Dohme Ltd. WO2005049601 (2005)
  • Zheng X, Hodgetts KJ, Brielmann H, et al. From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist. Bioorg Med Chem Lett 2006;16:5217-21
  • A Phase II clinical trial comparing NGD-8243/MK-2295 to ibuprofen in patients with postoperative dental pain. Available from: http://clinicaltrialsgov./show/NCT00387140
  • Jetter MC, Youngman MA, McNally JJ, et al. N-Isoquinolin-5-yl-N’-aralkyl-urea and amide antagonists of human vanilloid receptor 1. Bioorg Med Chem Lett 2004;14:3053-6
  • Gomtsyan AR, Bayburt EK, Schmiedt RG, et al. 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. J Med Chem 2005;48:744-52
  • El Kouhen R, Surowy CS, Bianchi BR, et al. 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. J Pharmacol Exp Ther 2005;314:400-9
  • Honore P, Wismer CT, Mikusa J, et al. A-425619 [1-isoquinolin-5-yl-3- (4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J Pharmacol Exp Ther 2005;314:410-21
  • Rami HK, Thompson M, Wyman P, et al. Discovery of small molecule antagonists of TRPV1. Bioorg Med Chem Lett 2004;14:3631-4
  • Rami HK, Thompson M, Wyman P, et al. Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett 2006;16:3287-91
  • Gunthorpe MJ, Rami HK, Jerman JC, et al. Identification and characterization of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology 2004;46:133-49
  • Doherty EM, Fotsch C, Bo Y, et al. Discovery of potent, orally available vanilloid receptor-1 antagonists Structure-activity relationship of N-aryl cinnamides. J Med Chem 2005;48:71-90
  • No pain, some gain. New drugs aimed at specific neuron targets promise relief from chronic agony. A recent survey shows that most patients with chronic pain find their over-the-counter medications ineffective. Available from: http://businessweek.com/magazine/content/05_03/b3916089_mz018.htm
  • Simone DA, Nolano M, Johnson T, et al. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 1998;18:8947-59
  • Dasgupta P, Chandiramani V, Parkinson MC, et al. Treating the human bladder with capsaicin: is it safe? Eur J Urol 1998;33:28-31
  • Silva C, Avelino A, Souto-Moura C, Cruz F. A light- and electron-microscopic histopathological study of human bladder mucosa after intravesical resiniferatoxin application. BJU Int 2001;88:355-60
  • Chancellor MB. Should we be using chili peppers extracts to treat the overactive bladder? J Urol 1997;158:2097
  • Andersson KE. Overactive bladder: pharmacological aspects. Scand J Urol Nephrol 2002;210:72-81
  • El-Mahrouky AS, Elashry OM, Emran MA. The effect of intravesical capsaicin and resiniferatoxin in neurogenic bladder dysfunction. Adv Exp Med Biol 2002;539:359-79
  • Forst T, Pohlman T, Kunt T, et al. The influence of local capsaicin treatment on small nerve fiber function and neurovascular control in symptomatic diabetic neuropathy. Acta Diabetol 2002;39:1432-9
  • Lauria G, Morbin M, Lombardi R, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and painful neuropathies. J Periph Nerv Syst 2006;11:262-71
  • Herman RM, Brower JB, Stoddard GD, et al. Prevalence of somatic small nerve fiber neuropathy in obesity. Int J Obes 2007;31:226-35
  • Tender GC, Walbridge S, Olah Z, et al. Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation. J Neurosurg 2005;102:522-5
  • Brown DC, Iadarola MJ, Perkowski SZ, et al. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiol 2005;103:1052-9
  • Aucheron Pharma is to conduct clinical trials with site-specific resiniferatoxin injections in patients with well localized chronic pain. Available from: www.acheuron.hu
  • New technique using old drug eliminated cancer pain in test animals. The National Cancer Institute plans clinical trials with site-specific resiniferatoxin injections in patients with intractable cancer pain. Available from: www.cancerpage.com/news/article.asp?id=7032
  • Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007;449:607-10
  • Chizh BA, O'Donnell MB, Napolitano A, et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 2007;132:132-41
  • Clinicaltrials.gov: migraine trial with SB-705498 was terminated due to disappointing clinical efficacy. Available from: www.clinicaltrials.gov/ct2/results?cond=%22migraine+disorders
  • Gavva N. The capsaicin receptor TRPV1: is it a pain transducer or a regulator of body temperature? Poster# 400.9/0022 Society for Neuroscience Meeting Planner. Online. San Diego, CA [2007]. Available from: www.sfn.org
  • Cui M, Honore P, Zhong C, et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci 2006;26:9385-93
  • Szallasi A, Blumberg PM. Complex regulation of TRPV1 by vanilloids. In: Heller S, Liedtke W, editors. TRP ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Heller S, Liedtke W, editors. Boca Raton: CRC Press; 2006. p. 85-104
  • Sculptoreanu A, De Groat WC, Buffington CA, Birder LA. Protein kinase C contributes to abnormal capsaicin responses in DRG neurons from cats with feline interstitial cystitis. Neurosci Lett 2005;381:42-6
  • Szallasi A. The vanilloid receptor TRPV1: diversity of behavior of exogenous ligands. Spring Pain Research Conference, Grand Caymans; 2006
  • Abbott Laboratories. US2005085512 (2005)
  • Daewoong Pharmaceutical Co., Ltd. WO2006080821 (2006)
  • Euro-celtique SA. WO2005030766 (2005)
  • Euro-celtique SA. WO2003066595 (2003)
  • Euro-celtique SA. WO2004011441 (2004)
  • Euro-celtique SA. WO2004058754 (2004)
  • Euro-celtique SA. WO2005009988 (2005)
  • Euro-celtique SA. WO2005009987 (2005)
  • Euro-celtique SA. WO2005012287 (2005)
  • Euro-celtique SA. WO2005066130 (2005)
  • Euro-celtique SA. WO2005030753 (2005)
  • Euro-celtique SA. WO2004002983 (2004)
  • Euro-celtique SA. WO2003074520 (2003)
  • Euro-celtique SA. WO2004029031 (2004)
  • Euro-celtique SA. WO2005004866 (2005)
  • Glaxo Group Ltd. WO2005016922 (2005)
  • Glaxo Group Ltd. WO2005016915 (2005)
  • Gruenenthal GmbH. WO2006122769 (2006)
  • Gruenenthal GmbH. WO2006122770 (2006)
  • Merck Sharp & Dohme Ltd. WO2005051390 (2005)
  • Neurogen Corp. WO2005007648 (2005)
  • Neurogen Corp. WO2005009980 (2005)
  • Neurogen Corp. WO2006078992 (2006)
  • Neurogen Corp. WO2006026135 (2006)
  • Neurogen Corp. WO2006071538 (2006)
  • Neurogen Corp. WO2006065872 (2006)
  • Neurogen Corp. WO2005007646 (2005)
  • Renovis, Inc. WO2005032493 (2005)
  • Abbott Laboratories. WO2006065646 (2006)
  • Merck Sharp & Dohme Ltd. WO2004074290 (2004)
  • Merck Sharp & Dohme Ltd. WO2004099177 (2004)
  • Neurogen Corp. WO2005009982 (2005)
  • Neurogen Corp. WO2004055003 (2004)
  • Neurogen Corp. WO2004054582 (2004)
  • Neurogen Corp. WO2006076646 (2006)
  • Neurogen Corp. WO2003062209 (2003)
  • Neurogen Corp. WO2004055004 (2004)
  • Neurogen Corp. WO2005023807 (2005)
  • Neurogen Corp. WO2005087227 (2005)
  • Neurogen Corp. WO2005084401 (2005)
  • Neurogen Corp. WO2005007652 (2005)
  • Neurogen Corp. WO2006081388 (2006)
  • Neurogen Corp. WO2006042289 (2006)
  • Neurogen Corp. WO2005042498 (2005)
  • Neurogen Corp. WO2005086968 (2005)
  • Renovis, Inc. WO2005066171 (2005)
  • Abbott Laboratories. US2003158198 (2003)
  • Abbott Laboratories. WO2004111009 (2004)
  • Abbott Laboratories. WO2006063178 (2006)
  • Abbott Laboratories. WO2006122250 (2006)
  • Amorepacific Corp. WO2006101318 (2006)
  • Astrazeneca AB. WO2004089881 (2004)
  • Astrazeneca AB. WO2004089877 (2004)
  • Bayer Healthcare AG. JP2003192587 (2003)
  • Bayer Healthcare AG. JP2003192659 (2003)
  • Bayer Healthcare AG. JP2003192660 (2003)
  • Bayer Healthcare AG. WO2003014064 (2003)
  • Bayer Healthcare AG. WO2003095420 (2003)
  • Bayer Healthcare AG. WO2005044786 (2005)
  • Bayer Healthcare AG. WO2005044802 (2005)
  • Bayer Healthcare AG. WO2005103018 (2005)
  • Bayer Healthcare AG. WO2005040100 (2005)
  • Bayer Healthcare AG. WO2004072020 (2004)
  • Bayer Healthcare AG. WO2004052845 (2004)
  • Bayer Healthcare AG. WO2004052846 (2004)
  • Glaxo Group Ltd. WO2004078749 (2004)
  • Glaxo Group Ltd. WO2004078101 (2004)
  • Glaxo Group Ltd. WO2004024710 (2004)
  • Glaxo Group Ltd. WO2004007459 (2004)
  • Janssen Pharmaceutica NV. WO2003097586 (2003)
  • Merck Sharp & Dohme Ltd. WO2003080578 (2003)
  • Merck Sharp & Dohme Ltd. WO2005028445 (2005)
  • Smithkline Beecham PLC. WO2003022809 (2003)
  • Smithkline Beecham PLC. WO2003053945 (2003)
  • Amgen, Inc. WO2005033105 (2005)
  • Amorepacific Corp. WO2006101321 (2006)
  • Glaxo Group Ltd. WO2003068749 (2003)
  • Gruenenthal GmbH. WO2007045462 (2007)
  • Janssen Pharmaceutica NV. WO2006058338; (2006)
  • Janssen Pharmaceutica NV. WO2006102645 (2006)
  • Merck Sharp & Dohme Ltd. WO2004046133 (2004)
  • Pfizer, Inc. WO2005095329 (2005)
  • Pfizer, Inc. WO2006103503 (2006)
  • Pfizer, Inc. WO2006016218 (2006)
  • Pfizer, Inc. WO2006051378 (2006)
  • Pfizer, Inc. WO2006097817 (2006)
  • Pfizer, Inc. US2006100460 (2006)
  • Renovis, Inc. US2005222200 (2005)
  • Renovis, Inc. WO2005046683 (2005)
  • Renovis, Inc. WO2006093832 (2006)
  • Sanofi-Aventis. WO2006072736 (2006)
  • Sanofi-Aventis. WO2007010144 (2007)
  • Sanofi-Aventis. WO2007010138 (2007)
  • Yamanouchi Pharmaceutical Co. Ltd. WO2004110986 (2004)
  • AstraZeneca AB. WO2004096784 (2004)
  • AstraZeneca AB. WO2006038871 (2006)
  • Astrazeneca AB. WO2006068592 (2006)
  • Astrazeneca AB. WO2006068618 (2006)
  • Astrazeneca AB. WO2006068593 (2006)
  • Janssen Pharmaceutica NV. WO2004069792 (2004)
  • Japan Tobacco, Inc. WO2006006741 (2006)
  • Akzo Nobel NV. US2007112034 (2007)
  • Akzo Nobel NV. US2007105920 (2007)
  • Astrazeneca AB. WO2004100865 (2004)
  • AstraZeneca AB. WO2006033620 (2006)
  • NV Organon. WO2007054480 (2007)
  • Merck Sharp & Dohme Ltd. WO2005049613 (2005)
  • Merck Sharp & Dohme Ltd. WO2006100520 (2006)
  • Merck Sharp & Dohme Ltd. WO2006120481 (2006)
  • Merck Sharp & Dohme Ltd. Neurogen Corp. WO2006122200 (2006)
  • Novartis A-G. Novartis PharmaGmbH. WO2005121116 (2005)

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