Novel 3-oxazolidinedione-6-aryl-pyridinones as potent, selective, and orally active EP3 receptor antagonists

ACS Medicinal Chemistry Letters

Volumn 1, Issue 7, 2010, Pages 316-320

  Jin, Jian ^a,b   Morales Ramos, Ángel ^a   Eidam, Patrick ^a   Mecom, John ^a   Li, Yue ^a   Brooks, Carl ^a   Hilfiker, Mark ^a   Zhang, David ^a   Wang, Ning ^a   Shi, Dongchuan ^a   Tseng, Pei San ^a   Wheless, Karen ^a   Budzik, Brian ^a   Evans, Karen ^a   Jaworski, Jon Paul ^a   Jugus, Jack ^a   Leon, Lisa ^a   Wu, Charlene ^a   Pullen, Mark ^a   Karamshi, Bhumika ^a   Rao, Parvathi ^a   Ward, Emma ^a   Laping, Nicholas ^a   Evans, Christopher ^a   Leach, Colin ^a   Holt, Dennis ^a   Su, Xin ^a   Morrow, Dwight ^a   Fries, Harvey ^a   Thorneloe, Kevin ^a   Edwards, Richard ^a   more..

^a GLAXOSMITHKLINE   (United States)

^b UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

3 oxazolidinedione 6 aryl pyridinones; and orally active antagonists; EP3 receptor; novel; potent; selective

Indexed keywords

GLUTATHIONE; PROSTAGLANDIN E RECEPTOR; PROSTAGLANDIN E2 RECEPTOR EP3; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; PYRIDONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; NONHUMAN; OVERACTIVE BLADDER; PRIORITY JOURNAL; RAT;

EID: 77958093761     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml100077x     Document Type: Article

References (27)

1. Narumiya, S.; Sugimoto, Y.; Ushikubi, F. Prostanoid receptors: Structures, properties, and functions Physiol. Rev. 1999, 79, 1193-1226
2. Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, M. D. Prostanoid receptors: Subtypes and signaling Annu. Rev. Pharmacol. Toxicol. 2001, 41, 661-690
3. Sugimoto, Y.; Narumiya, S. Prostaglandin E receptors J. Biol. Chem. 2007, 282, 11613-11617
4. Steers, W. D. Pathophysiology of overactive bladder and urge urinary incontinence Rev. Urol. 2002, 4 (Suppl. 4) S7-S18
5. McCafferty, G. P.; Misajet, B. A.; Laping, N. J.; Edwards, R. M.; Thorneloe, K. S. Enhanced bladder capacity and reduced prostaglandin E2-mediated bladder hyperactivity in EP3 receptor knockout mice Am. J. Physiol. Renal Physiol. 2008, 295, F507-F514
6. Maggi, C. A. Prostanoids as local modulators of reflex micturition Pharmacol. Res. 1992, 25, 13-20
7. Kim, J. C.; Park, E. Y.; Hong, S. H.; Seo, S. I.; Park, Y. H.; Hwang, T. K. Changes of urinary nerve growth factor and prostaglandins in male patients with overactive bladder symptom Int. J. Urol. 2005, 12, 875-880
8. Kim, J. C.; Park, E. Y.; Seo, S. I.; Park, Y. H.; Hwang, T. K. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder J. Urol. 2006, 175, 1773-1776
9. Wang, C.; Li, G. W.; Huang, L. Y. Prostaglandin E2 potentiation of P2 Ã - 3 receptor mediated currents in dorsal root ganglion neurons Mol. Pain 2007, 3, 22
10. Wibberley, A. Overactive bladder: Targeting prostaglandins in sensory pathways Drug Discovery Today: Ther. Strategies 2005, 2, 7-13
11. Juteau, H.; Gareau, Y.; Labelle, M.; Sturino, C. F.; Sawyer, N.; Tremblay, N.; Lamontagne, S.; Carriere, M. C.; Denis, D.; Metters, K. M. Structure-activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor Bioorg. Med. Chem. 2001, 9, 1977-1984 (Pubitemid 32739185)
12. Gallant, M.; Carriere, M. C.; Chateauneuf, A.; Denis, D.; Gareau, Y.; Godbout, C.; Greig, G.; Juteau, H.; Lachance, N.; Lacombe, P.; Lamontagne, S.; Metters, K. M.; Rochette, C.; Ruel, R.; Slipetz, D.; Sawyer, N.; Tremblay, N.; Labelle, M. Structure-activity relationship of biaryl acylsulfonamide analogues on the human EP(3) prostanoid receptor Bioorg. Med. Chem. Lett. 2002, 12, 2583-2586
13. Belley, M.; Chan, C. C.; Gareau, Y.; Gallant, M.; Juteau, H.; Houde, K.; Lachance, N.; Labelle, M.; Sawyer, N.; Tremblay, N.; Lamontagne, S.; Carriere, M. C.; Denis, D.; Greig, G. M.; Slipetz, D.; Gordon, R.; Chauret, N.; Li, C.; Zamboni, R. J.; Metters, K. M. Comparison between two classes of selective EP(3) antagonists and their biological activities Bioorg. Med. Chem. Lett. 2006, 16, 5639-5642
14. Zhou, N.; Zeller, W.; Krohn, M.; Anderson, H.; Zhang, J.; Onua, E.; Kiselyov, A. S.; Ramirez, J.; Halldorsdottir, G.; Andresson, T.; Gurney, M. E.; Singh, J. 3,4-Disubstituted indole acylsulfonamides: A novel series of potent and selective human EP3 receptor antagonists Bioorg. Med. Chem. Lett. 2009, 19, 123-126
15. Zhou, N.; Zeller, W.; Zhang, J.; Onua, E.; Kiselyov, A. S.; Ramirez, J.; Palsdottir, G.; Halldorsdottir, G.; Andresson, T.; Gurney, M. E.; Singh, J. 3-Acrylamide-4-aryloxyindoles: Synthesis, biological evaluation and metabolic stability of potent and selective EP(3) receptor antagonists Bioorg. Med. Chem. Lett. 2009, 19, 1528-1531
16. Singh, J.; Zeller, W.; Zhou, N.; Hategen, G.; Mishra, R.; Polozov, A.; Yu, P.; Onua, E.; Zhang, J.; Zembower, D.; Kiselyov, A.; Ramirez, J. L.; Sigthorsson, G.; Bjornsson, J. M.; Thorsteinsdottir, M.; Andresson, T.; Bjarnadottir, M.; Magnusson, O.; Fabre, J. E.; Stefansson, K.; Gurney, M. E. Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding ACS Chem. Biol. 2009, 4, 115-126
17. 3 cDNA. For assay details, see the Supporting Information.
18. i calculations are detailed in the Supporting Information.
19. The biological assay results in this paper are a mean of at least two determinations with a standard deviation of <±0.3.
20. Compounds reported in this paper are all racemic.
21. For assay details, see the Supporting Information.
22. PK parameters are averaged values from studies using Sprague-Dawley rats (n = 3) dosed at 1 mg/kg (iv) and 2 mg/kg (po).
23. Su, X.; Leon, L. A.; Wu, C. W.; Morrow, D. M.; Jaworski, J. P.; Hieble, J. P.; Lashinger, E. S.; Jin, J.; Edwards, R. M.; Laping, N. J. Modulation of bladder function by prostaglandin EP3 receptors in the central nervous system Am. J. Physiol. Renal Physiol. 2008, 295, F984-F994
24. Wibberley, A.; McCafferty, G. P.; Evans, C.; Edwards, R. M.; Hieble, J. P. Dual, but not selective, COX-1 and COX-2 inhibitors, attenuate acetic acid-evoked bladder irritation in the anaesthetised female cat Br. J. Pharmacol. 2006, 148, 154-161
25. Li, Y. H.; Zhang, L.; Tseng, P.-S.; Zhang, Y.; Jin, Y.; Shen, J.; Jin, J. A facile one-pot synthesis of 3-unsubstituted-2,4-oxazolidinediones via in situ generation of carbamates from [alpha]-hydroxyesters using trichloroacetyl isocyanate Tetrahedron Lett. 2009, 50, 790-792
26. 3 receptors in the conscious rat Br. J. Pharmacol. 2009, 158, 372-381
27. 2 selectivity J. Med. Chem. 2005, 48, 3953-3979