Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate

Journal of Medicinal Chemistry

Volumn 50, Issue 15, 2007, Pages 3515-3527

  Doherty, Elizabeth M ^a   Fotsch, Christopher ^a   Bannon, Anthony W ^a   Bo, Yunxin ^a   Chen, Ning ^a   Dominguez, Celia ^b   Falsey, James ^a   Gavva, Narender R ^a   Katon, Jodie ^a   Nixey, Thomas ^a   Ognyanov, Vassil I ^a   Pettus, Liping ^a   Rzasa, Robert M ^a   Stec, Markian ^a   Surapaneni, Sekhar ^a   Tamir, Rami ^a   Zhu, Jiawang ^a   Treanor, James J S ^a   Norman, Mark H ^a  

^a AMGEN INC   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

4 OXOPYRIMIDINE DERIVATIVE; AMG 517; ANALGESIC AGENT; CALCIUM; CAPSAICIN; HETEROCYCLIC COMPOUND; N [4 [6 (4 TRIFLUOROMETHYLPHENYL)PYRIMIDIN 4 YLOXY]BENZOTHIAZOL 2 YL]ACETAMIDE; UNCLASSIFIED DRUG; VANILLOID RECEPTOR 1; VANILLOID RECEPTOR 1 ANTAGONIST;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CALCIUM TRANSPORT; CHO CELL; CONTROLLED STUDY; DRUG DETERMINATION; HYPERALGESIA; INFLAMMATION; NONHUMAN; PROTEIN EXPRESSION; RAT; STRUCTURE ACTIVITY RELATION;

ANALGESICS; ANIMALS; BENZOTHIAZOLES; CALCIUM; CHO CELLS; CRICETINAE; CRICETULUS; DOGS; DRUG STABILITY; HAPLORHINI; HUMANS; HYPERALGESIA; INFLAMMATION; MALE; MICROSOMES, LIVER; PAIN MEASUREMENT; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TRPV CATION CHANNELS;

EID: 34547560453     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm070190p     Document Type: Article

References (16)

1. (a) Appendino, G.; Munoz, E.; Fiebich, B. L. TRPV1 (Vanilloid receptor, Capsaicin receptor) Agonists and Antagonists. Expert Opin. Ther. Pat. 2003, 13, 1825-1837.
2. (b) Rami, K. H.; Gunthorpe, M. J. The Therapeutic Potential of TRPV1 (VR1) Antagonists: Clinical Answers Await. Drug Discovery Today 2004, 1, 97-104.
3. (c) Breitenbucher, G.; Chaplan, S. R.; Carruters, N. I. The TRPV1 Vanilloid Receptor: A Target for Therapeutic Intervention. In Ann. Rep. Med. Chem.; Doherty, A. M., Ed.; Elsevier Inc.: San Diego, 2005; Vol. 40, pp 185-198.
4. Norman, M. H.; Fotsch, C.; Doherty, E. M.; Bo, Y.; Chen, N.; Chakrabarti, P.; Gavva, N. R.; Nishimura, N.; Nixey, T.; Ognyanov, V. I.; Rzasa, R.; Stec, M.; Surapaneni, S.; Tamir, R.; Viswanadhan, V.; Zhu, J.; Treanor, J. J. S. Novel Vanilloid Receptor-1 Antagonists: 1. Conformationally Restricted Analogues of trans-Cinnamides. J. Med. Chem. 2007, 50, 3497-3514.
5. Chakrabarti, P. P.; Chen, N.; Doherty, E. M.; Dominguez, C.; Falsey, J. R.; Fotsh, C. H.; Hulme, C.; Katon, J.; Nixey, T.; Norman, M. H.; Ognyanov, V. I.; Pettus, L. H.; Rzasa, R. M.; Stec, M.; Wang, H.-L.; Zhu, J. (Amgen Inc.) Preparation of (aryloxy)pyrimidine and (aryloxy)pyridazine as vanilloid receptor ligands. WO 04014871, 2004.
6. Csikos, E.; Gonczi, C.; Podanyi, B.; Toth, G.; Hermecz, I. Regioselectivity in preparation of unsymmetrically substituted 3-aminoquinoxalin-2(1H)-ones. J. Chem. Soc., Perkin Trans. 1 1999 13, 1789-1793.
7. 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 (1), 71-90.
8. This observation is also consistent with the results of 6,6-fused heteroaromatic-containing urea TRPV1 antagonists reported by 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 (3), 744-752.
9. The effect on in vitro potency for these antagonists as a result of varying pH is beyond the scope of this discussion, but will be presented in more detail in a subsequent article.
10. Gavva, N. R.; Tamir, R.; Qu, Y.; Klionsky, L.; Zhang, T. J.; Immke, D.; Wang, J.; Zhu, D.; Vanderah, T. W.; Porreca, F.; Doherty, E. M.; Norman, M. H.; Wild, K. D.; Bannon, A. W.; Louis, J.-C.; Treanor, J. J. S. AMG 9810 [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with Antihyperalgesic Properties. J. Pharmacol. Exp. Ther. 2005, 313, 474-484.
11. Lewis, F. D.; Reddy, G. D.; Elbert, J. E.; Tillberg, B, E.; Meltzer, J. A.; Kojima, M. Lewis Acid Catalysis of Photochemical Reactions. 10. Spectroscopy and Photochemistry of 2-Quinolones and their Lewis Acid Complexes. J. Org. Chem. 1991, 56 (18), 5311-5318.
12. Compound 20 was incubated at a concentration of 10 μM with rat or human hepatocytes (1 million cells/mL) for 4 h at 37°C. Control incubations in the absence of cells were also carried out. Reactions were quenched with acetonitrile containing 0.05% formic acid. The supernatant was analyzed by reverse phase (YMC ODS-AQ, 4.6 x 250mm, 5 μm) HPLC-MS/MS with radiometric detection and ion trap mass spectrometry using electrospray ionization. Hydrolysis experiments were conducted with glucoronidase and/or sulfatase to confirm the presence of glucoronide and/or sulfate metabolites.
13. Stevens, J. R.; Pfister, K.; Wolf, F. J. Substituted Sulfaquinoxalines. I. The Isolation and Synthesis of 3-Hydroxy-2-sulfanilamidoquinoxaline and of Related Quinoxalines J. Am. Chem. Soc. 1946, 68 (6), 1035-1039.
14. Tan, H.; Semin, D.; Wacker, M.; Cheetham, J. An Automated Screening Assay for Determination of Aqueous Equilibrium Solubility Enabling SPR Study During Drug Lead Optimization. JALA 2005, 10 (6), 364-373.
15. Gavva, N. R.; Bannon, A. W.; Immke, D. C.; Tamir, R.; Klionsky, L.; Hever, G.; Wang, J.; Davis, J.; Zajic, G.; Arik, L.; Shi, L.; Bak, A.; Surapaneni, S.; Hovland, D. N., Jr.; Louis, J.-C.; Norman, M. H.; Magal, E.; Treanor, J. J. S. Preclinical Pharmacology of AMG 517: A Novel TRPV1 Antagonist in the Clinic, Society for Neuroscience annual meeting, Atlanta, GA, 2006, poster no. 51.21/ M13.
16. McKillop, A.; Chattopadhyay, S. K.; Henderson, A.; Avendano, C. Applications of Ethyl Carboethoxyformimidate to Heterocyclic Synthesis. Preparation of Condensed Pyrazinones and 1,4-Oxazinones. Synthesis 1997, 3, 301-304.