Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists

Journal of Medicinal Chemistry

Volumn 53, Issue 8, 2010, Pages 3330-3348

  Blum, Charles A ^a   Caldwell, Timothy ^a   Zheng, Xiaozhang ^a   Bakthavatchalam, Rajagopal ^a   Capitosti, Scott ^a   Brielmann, Harry ^a   De Lombaert, Stéphane ^a   Kershaw, Mark T ^a   Matson, David ^a   Krause, James E ^a   Cortright, Daniel ^a   Crandall, Marci ^a   Martin, William J ^b   Murphy, Beth Ann ^b   Boyce, Susan ^b   Jones, A Brian ^b   Mason, Glenn ^b   Rycroft, Wayne ^b   Perrett, Helen ^b   Conley, Rachael ^b   Burnaby Davies, Nicola ^b   Chenard, Bertrand L ^a   Hodgetts, Kevin J ^a,c   more..

^a NEUROGEN CORPORATION   (United States)

^b Merck Sharp & Dohme Limited   (United Kingdom)

^c Galenea Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(4 TRIFLUOROMETHYLPHENYL)[7 (3 TRIFLUOROMETHYLPYRIDIN 2 YL)QUINAZOLIN 4 YL]AMINE; (5 TRIFLUOROMETHYLPYRIDIN 2 YL)[7 (3 TRIFLUOROMETHYLPYRIDIN 2 YL)QUINAZOLIN 4 YL]AMINE; (6 TRIFLUOROMETHYLPYRIDIN 3 YL)[7 (3 TRIFLUOROMETHYLPYRIDIN 2 YL)QUINAZOLIN 4 YL]AMINE; 1 (2 BROMOPHENYL) 3 [1 (5 TRIFLUOROMETHYL 2 PYRIDINYL) 3 PYRROLIDINYL]UREA; 1 (5 TERT BUTYL 2,3 DIHYDRO 1H INDEN 1 YL) 3 (1H INDAZOL 4 YL UREA); 7 [3 (TRIFLUOROMETHYL)PYRIDIN 2 YL] N [5 (TRIFLUOROMETHYL)PYRIDIN 2 YL] 1,8 NAPHTHYRIDIN 4 AMINE; ABT 517; ANALGESIC AGENT; ANTIINFLAMMATORY AGENT; ANTINOCICEPTIVE AGENT; CALCIUM CHANNEL L TYPE; CAPSAICIN; CARRAGEENAN; FREUND ADJUVANT; HETEROCYCLIC COMPOUND; INDAZOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE 3; N [4 [6 [4 (TRIFLUOROMETHYL)PHENYL] 4 PYRIMIDINYLOXY]BENZOTHIAZOL 2 YL]ACETAMIDE; NAPHTHYRIDINE DERIVATIVE; NAPROXEN; PICOLINE DERIVATIVE; PYRIMIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; RECEPTOR BLOCKING AGENT; TRIACETIN; UNCLASSIFIED DRUG; UREA DERIVATIVE; VANILLOID RECEPTOR 1;

ANIMAL CELL; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CHRONIC INFLAMMATION; CHRONIC PAIN; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG PENETRATION; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; HYPERALGESIA; IC 50; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANALGESICS; ANIMALS; BIOLOGICAL AVAILABILITY; CAPSAICIN; CERCOPITHECUS AETHIOPS; COS CELLS; HOT TEMPERATURE; HUMANS; HYPERALGESIA; INFLAMMATION; MICROSOMES, LIVER; NAPHTHYRIDINES; PAIN; PYRAZINES; PYRIDINES; PYRIMIDINES; QUINAZOLINES; QUINOLINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRPV CATION CHANNELS;

EID: 77951143988     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100051g     Document Type: Article

References (48)

1. Caterina, M. J.; Schumaker, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway Nature 1997, 389, 816-824 (Pubitemid 27462969)
2. Zygmunt, P. M.; Petersson, J.; Andersson, D. A.; Chuang, H.; Sørg'rd, M.; Di Marzo, V.; Julius, D.; Högestätt, E. D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide Nature 1999, 400, 452-457 (Pubitemid 29361798)
3. Huang, S. M.; Bisogno, T.; Trevisani, M.; Al-Hayani, A.; De Petrocellis, L.; Fezza, F.; Tognetto, M.; Petros, T. J.; Krey, J. F.; Chu, C. J.; Miller, J. D.; Davies, S. N.; Geppetti, P.; Walker, J. M.; Di Marzo, V. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 8400-8405 (Pubitemid 34651064)
4. Hwang, S. W.; Cho, H.; Kwak, J.; Lee, S.-J.; Kang, C.-J.; Jung, J.; Cho, S.; Min, K. H.; Suh, Y.-G.; Kim, D.; Oh, U. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6155-6160 (Pubitemid 30367539)
5. Siemens, J.; Zhou, S.; Piskorowski, R.; Nikai, T.; Lumpkin, E. A.; Basbaum, A.; I.; King, D.; Julius, D. Spider toxins activate the capsaicin receptor to produce inflammatory pain Nature 2006, 444, 208-212 (Pubitemid 44722061)
6. Cuypers, E.; Yanagihara, A.; Karlsson, E.; Tytgat, J. Jellyfish and other cnidarian envenomations cause pain by affecting TRPV1 channels FEBS Lett. 2006, 580, 5728-5732 (Pubitemid 44500677)
7. Caterina, M. J.; Leffler, A.; Malmberg, A. B.; Martin, W. J.; Trafton, J.; Petersen-Zeitz, K. R.; Koltzenburg, M.; Basbaum, A. I.; Julius, D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor Science 2000, 288, 306-313 (Pubitemid 30226186)
8. Davis, J. B.; Gray, J.; Gunthorpe, M. J.; Hatcher, J. P.; Davey, P. T.; Overend, P.; Harries, M. H.; Latcham, J.; Clapham, C.; Atkinson, K.; Hughes, S. A.; Rance, K.; Grau, E.; Harper, A. J.; Pugh, P. L.; Rogers, D. C.; Bingham, S.; Randall, A.; Sheardown, S. A. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia Nature 2000, 405, 183-187 (Pubitemid 30313536)
9. Szallasi, A.; Cortright, D. N.; Blum, C. A.; Eid, S. R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept Nat. Rev. Drug Discovery 2007, 6, 357-372 (Pubitemid 46705200)
10. Westaway, S. M. The potential of transient receptor potential vanilloid type 1 channel modulators for the treatment of pain J. Med. Chem. 2007, 50, 2589-2596 (Pubitemid 46896064)
11. Gharat, L.; Szallasi, A. Medicinal chemistry of the vanilloid (capsaicin) TRPV1 receptor: current knowledge and future perspectives Drug Dev. Res. 2007, 68, 477-497 (Pubitemid 351312141)
12. Gunthorpe, M. J.; Hannan, S. L.; Smart, D.; Jerman, J. C.; Arpino, S.; Smith, G. D.; Brough, S.; Wright, J.; Egerton, J.; Lappin, S. C.; Holland, V. A.; Winborn, K.; Thompson, M.; Rami, H. K.; Randall, A. D.; Davis, J. B. Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-activation of the receptor J. Pharmacol. Exp. Ther. 2007, 321, 1183-1192 (Pubitemid 46762715)
13. Rami, H. K.; Thompson, M.; Wyman, P.; Jerman, J. C.; Egerton, J.; Brough, S.; Stevens, A. J.; Randall, A. D.; Smart, D.; Gunthorpe, M. J.; Davis, J. B. Discovery of small molecule antagonists of TRPV1 Bioorg. Med. Chem. Lett. 2004, 14, 3631-3634 (Pubitemid 38760052)
14. Rami, H. K.; Thompson, M.; Stemp, G.; Fell, S.; Jerman, J. C.; Stevens, A. J.; Smart, D.; Sargent, B.; Sanderson, D.; Randall, A. D.; Gunthorpe, M. J.; Davis, J. B. Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development Bioorg. Med. Chem. Lett. 2006, 16, 3287-3291 (Pubitemid 43732339)
15. Chizh, B. A.; O'Donnell, M. B.; Napolitano, A.; Wang, J.; Brooke, A. C.; Aylott, M. C.; Bullman, J. N.; Gray, E. J.; Lai, R. Y.; Williams, P. M.; Appleby, J. M. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans Pain 2007, 132, 132-141 (Pubitemid 47494566)
16. Doherty, E. M.; Fotsch, C.; Bo, Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han, N.; Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M. H.; Treanor, J. J. S. Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N -aryl cinnamides J. Med. Chem. 2005, 48, 71-90 (Pubitemid 40105250)
17. Norman, M. H.; Zhu, J.; Fotsch, C.; Bo, Y.; Chen, N.; Chakrabarti, P.; Doherty, E. M.; Gavva, N. R.; Nishimura, N.; Nixey, T.; Ognyanov, V. I.; Rzasa, R. M.; Stec, M.; Surapaneni, S.; Tamir, R.; Viswanadhan, V. N.; Treanor, J. J. Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues J. Med. Chem. 2007, 50, 3497-3514 (Pubitemid 47195459)
18. Doherty, E. M.; Fotsch, C.; Bannon, A. W.; Bo, Y.; Chen, N.; Dominguez, C.; Falsey, J.; Gavva, N. R.; Katon, J.; Nixey, T.; Ognyanov, V. I.; Pettus, L.; Rzasa, R. M.; Stec, M.; Surapaneni, S.; Tamir, R.; Zhu, J.; Treanor, J. J.; Norman, M. H. Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate J. Med. Chem. 2007, 50, 3415-3527 (Pubitemid 47195460)
19. Wang, H.-L.; Katon, J.; Balan, C.; Bannon, A. W.; Bernard, C.; Doherty, E. M.; Dominguez, C.; Gavva, N. R.; Gore, V.; Ma, V.; Nishimura, N.; Surapaneni, S.; Tang, P.; Tamir, R.; Thiel, O.; Treanor, J. J.; Norman, M. H. Novel vanilloid receptor-1 antagonists: 3. Identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties J. Med. Chem. 2007, 50, 3428-3539 (Pubitemid 47195461)
20. Gavva, N. R.; Treanor, J. J. S.; Garami, A.; Fang, L.; Surapaneni, S.; Akrami, A.; Alvarez, F.; Bak, A.; Darling, M.; Gore, A.; Jang, G. R.; Kesslak, J. P.; Ni, L.; Norman, M. H.; Palluconi, G.; Rose, M. J.; Salfi, M.; Tan, E.; Romanovsky, A. A.; Banfield, C.; Davar, G. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans Pain 2008, 136, 202-210
21. Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner, R. J.; Didomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.; Drizin, I.; Hannick, S. M.; Macri, B. S.; McDonald, H. A.; Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.; Stewart, K. D.; Oie, T.; Jarvis, M. F.; Surowy, C. S.; Faltynek, C. R.; Lee, C.-H. 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, 744-752
22. Gomtsyan, A.; Bayburt, E. K.; Keddy, R.; Turner, S. C.; Jinkerson, T. K.; DiDomenico, S.; Perner, R. J.; Koenig, J. R.; Drizin, I.; McDonald, H. A.; Surowy, C. S.; Honore, P.; Mikusa, J.; Marsh, K. C.; Wetter, J. M.; Faltynek, C. R.; Lee, C.-H. α-Methylation at benzylic fragment of N -aryl- N′-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model Bioorg. Med. Chem. Lett. 2007, 17, 3894-3899
23. Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Surowy, C. S.; Honore, P.; Marsh, K. C.; Hannick, S. M.; McDonald, H. A.; Wetter, J. M.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R.; Lee, C. H. Identification of (R)-1-(5- tert -butyl-2,3-dihydro-1 H -inden-1-yl)-3-(1 H -indazol-4-yl)urea (ABT-102) as a potent TRPV1 antagonist for pain management J. Med. Chem. 2008, 51, 392-395 (Pubitemid 351252266)
24. Surowy, C. S.; Neelands, T. R.; Bianchi, B. R.; McGaraughty, S.; El Kouhen, R.; Han, P.; Chu, K. L.; McDonald, H. A.; Vos, M.; Niforatos, W.; Bayburt, E. K.; Gomtsyan, A.; Lee, C. H.; Honore, P.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R. ABT-102 ((R)-(5- tert -butyl-2,3-dihydro-1 H -inden-1-yl)-3-(1 H -indazol-4-yl)-urea) blocks polymodal activation of TRPV1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo J. Pharmacol. Exp. Ther. 2008, 326, 879-888
25. Zheng., X.; Hodgetts, K. J.; Brielmann, H.; Hutchison, A.; Burkamp, F.; Jones, A. B.; Blurton, P.; Clarkson, R.; Chandrasekhar, J.; Bakthavatchalam, R.; De Lombaert, S.; Crandall, M.; Cortright, D.; Blum, C. A. From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 (VR1) antagonist Bioorg. Med. Chem. Lett. 2006, 16, 5217-5221 (Pubitemid 44247688)
26. DeSimone, R. W.; Hodgetts, K.; Krause, J. E.; White, G. PCT WO 02/08221, 2002.
27. Bakthavatchalam, R.; Hutchison, A.; DeSimone, R. W.; Hodgetts, K.; Krause, J. E.; White, G. U.S. Patent 6,723,730, 2004.
28. Other groups reporting on the arylurea series: Sun, Q.; Tafesse, L.; Islam, K.; Zhou, X.; Victory, S. F.; Zhang, C.; Hachicha, M.; Schmid, L. A.; Patel, A.; Rotshteyn, Y.; Valenzano, K. J.; Kyle, D. J. 4-(2-Pyridyl)piperazine- 1-carboxamides: potent vanilloid receptor 1 antagonists Bioorg. Med. Chem. Lett. 2003, 13, 3611-3616 (Pubitemid 37150471)
29. Tafesse, L.; Sun, Q.; Schmid, L. A.; Valenzano, K. J.; Rotshteyn, Y.; Su, X.; Kyle, D. J. Synthesis and evaluation of pyridazinylpiperazines as vanilloid receptor 1 antagonists Bioorg. Med. Chem. Lett. 2004, 14, 5513-5519
30. Swanson, D. M.; Dubin, A. E.; Shah, C.; Nasser, N.; Chang, L.; Dax, S. L.; Jetter, M.; Breitenbrucher, J. G.; Codd, E. E.; Lee, D. H.; Zhang, S.-P.; Chaplan, S. R.; Carruthers, N. I. 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 J. Med. Chem. 2005, 48, 1857-1872
31. Pomonis, J. D.; Harrison, J. E.; Lilly, M.; Bristol, D. R.; Valenzano, K. J.; Walker, K. N -(4-Tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl) tetrahydropyrazine-1(2 H)-carbox-amide (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, 387-393
32. Valenzano, K. J.; Grant, E. R.; Wu, G.; Hachicha, M.; Schmid, L.; Tafesse, L.; Sun, Q.; Rotshteyn, Y.; Francis, J.; Limberis, J.; Malik, S.; Whittemore, E. R.; Hodges, D. N -(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2- yl)tetrahydropyrazine-1(2 H)-carbox-amide (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, 377-386
33. Blum, C. A.; Zheng, X.; Brielmann, H.; Hodgetts, K. J.; Bakthavatchalam, R.; Chandrasekhar, J.; Krause, J. K.; Cortright, D.; Matson, D.; Crandall, M.; Ngo, C. K.; Fung, L.; Day, M.; Kershaw, M.; De Lombaert, S.; Chenard, B. L. Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution Bioorg. Med. Chem. Lett. 2008, 18, 4573
34. As assessed by percentage of block of hERG potassium channels using an in vitro electrophysiological whole cell (Cos7) assay at a compound concentration of 3 μM.
35. Brent, R. L. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child Teratology 2001, 63, 106-112
36. Rewcastle, G. W.; Denny, W. A.; Showalter, H. D. H. Synthesis of 4-(phenylamino)pyrimidine derivatives as ATP-competitive protein kinase inhibitors with potential for cancer chemotherapy Curr. Org. Chem. 2000, 4, 679-706
37. Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. A highly catalytic robust palladium catalyzed cyanation of aryl bromides Tetrahedron Lett. 1999, 40, 8193-8195
38. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Pd-Catalyzed N-arylation of heteroarylamines Org. Lett. 2002, 4, 3481-3484
39. Cai, S. X.; Zhou, Z.-L.; Huang, J.-C.; Whittemore, E. R.; Egbuwoku, Z. O.; Lü, Y.; Hawkinson, J. E.; Woodward, R. M.; Weber, E.; Keana, J. F. W. Synthesis and structure-activity relationships of 1,2,3,4-tetrahydroquinoline-2, 3,4-trione 3-oximes: novel and highly potent antagonists for NMDA receptor glycine site J. Med. Chem. 1996, 39, 3248-3255
40. Ram, S.; Ehrenkaufer, R. E. Ammonium formate in organic synthesis: a versatile agent in catalytic hydrogen transfer reductions Synthesis 1988, 91-95
41. Anwer, M. K.; Sherman, D. B.; Roney, J. G.; Spatola, A. F. Applications of ammonium formate catalytic transfer hydrogenation. 6. Analysis of catalyst, donor quantity, and solvent effects upon the efficacy of dechlorination J. Org. Chem. 1989, 54, 1284-1289
42. Cheng, C.-C.; Yan, S.-J. The Friedlander synthesis of quinolines Org. React. 1982, 28
43. Atkinson, C. M.; Simpson, J. C. E.; Cinnolines., X. The preparation of 4-chloro-2-aminoacetophenone and related 4-hydroxycinnolines J. Chem. Soc. 1947, 232-237
44. Compounds were tested as previously described: Szallasi, A.; Blumberg, P. M.; Annicelli, L. L.; Krause, J. E.; Cortright, D. N. The cloned rat vanilloid receptor VR1 mediates both R-type binding and C-type calcium response in dorsal root ganglion neurons Mol. Pharmacol. 1999, 56, 581-587
45. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkinson, K. K.; Polli, J. W. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs J. Pharmacol. Exp. Ther. 2002, 303, 1029-1037
46. Percentage of parent compound remaining after 10 min: Compounds at 1 μM were incubated at 37 °C in the presence of 0.5 mg/mL male pooled rat liver microsomes, and NADPH was added to commence the reaction. After 0 and 10 min, aliquots were sampled and reactions terminated by dispensing into ice cold acetonitrile with an internal standard. Samples were centrifuged for 15 min at 3000 rpm and analyzed by LCMS using electrospray ionization detection. The disappearance of parent compound was determined by monitoring the M + 1 ion in selective ion mode. The percent parent remaining was calculated by the ratio of the signal response at 10 min to that at 0 min and corrected by using the internal standard recovery.
47. Carrageenan-induced thermal hyperalgesia model of acute inflammatory pain as described in the following: Field, M. J.; Oles, R. J.; Lewis, A. S.; McCleary, S.; Hughes, J.; Singh, L. Gabapentin (neurontin) and S -(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents Br. J. Pharmacol. 1997, 121, 1513-1522
48. Honore, P.; Chandran, P.; Hernandez, G.; Gauvin, D. M.; Mikusa, J. P.; Zhong, C.; Joshi, S. K.; Ghilardi, J. R.; Sevcik, M. A.; Fryer, R. M.; Segreti, J. A.; Banfor, P. N.; Marsh, K.; Neelands, T.; Bayburt, E.; Daanen, J. F.; Gomtsyan, A.; Lee, C. H.; Kort, M. E.; Reilly, R. M.; Surowy, C. S.; Kym, P. R.; Mantyh, P. W.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia Pain 2009, 142, 27-35