Discovery of novel aminothiadiazole amides as selective EP3 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4292-4295

  Hilfiker, Mark A ^a   Wang, Ning ^a   Hou, Xiaoping ^a   Du, Zhimin ^a   Pullen, Mark A ^a   Nord, Melanie ^a   Nagilla, Rakesh ^a   Fries, Harvey E ^a   Wu, Charlene W ^a   Sulpizio, Anthony C ^b   Jaworski, Jon Paul ^b   Morrow, Dwight ^b   Edwards, Richard M ^a   Jin, Jian ^a  

^a GLAXOSMITHKLINE   (United States)

^b Screening and Compound Profiling   (United States)

Author keywords

7 TM; EP receptor; EP3; PGE2; Prostaglandin; Prostenoid; Thiadiazole

Indexed keywords

AMINOTHIADIAZOLE; BENZOXAZINE DERIVATIVE; EP3 RECEPTOR; G PROTEIN COUPLED RECEPTOR; N ETHYLBENZOXAZINE; N METHYLBENZOXAZINE AMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOG; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; CHEMISTRY, PHARMACEUTICAL; DOGS; DRUG DESIGN; HUMANS; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PROTEIN BINDING; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, PROSTAGLANDIN E; RECEPTORS, PROSTAGLANDIN E, EP3 SUBTYPE; STRUCTURE-ACTIVITY RELATIONSHIP; THIADIAZOLES;

RATTUS;

EID: 67649990550     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.074     Document Type: Article

References (31)

1. Sugimoto Y., Namba T., Shigemoto R., Negishi M., Ichikawa A., and Narumaiya S. Am. J. Physiol. 266 (1994) F823
2. Riento K., and Ridley A.J. Nat. Rev. Mol. Cell Biol. 4 (2003) 446
3. Sharif N.A., and Xu S.X. J. Pharm. Pharmacol. 56 (2004) 197
4. Hamon M., Berthaut J., Wisner A., Dray F., Descomps B., and Dao H.T. Prostaglandins 46 (1993) 251
5. Maruyama, T.; Kobayashi, M.; Nonaka, S.; Okada, H.; Konemura, T. WO Patent 2005000356 A1, 2005; Chem. Abstr. 2005, 14258. see also Ref. 10.
6. Soll A.H. J. Clin. Invest. 65 (1980) 1222
7. Takeuchi K., Svanes K., Critchlow J., Magee D., and Silen W. Proc. Soc. Exp. Biol. Med. 170 (1982) 398
8. Main I.H.M., and Whittle B.J.R. Eur. J. Pharmacol. 26 (1974) 204
9. Nylander O., Berhlindh T., and Obrink K.J. Am. J. Physiol. 250 (1986) G607
10. Sugimoto Y., Namba T., Honda A., Hayashi Y., Negishi M., Ichikawa A., and Narumiya S. J. Biol. Chem. 267 (1992) 6463
11. Ek M., Arias C., Sawchenko P., and Ericsson-Dahlstrand A. J. Comp. Neurol. 428 (2000) 5
12. For reviews, see:. Narumaiya S., Sugimoto Y., and Ushikubi Y. Physiol. Rev. 79 (1999) 1193
13. Breyer R.M., Bagdassarian C.K., Myers S.A., and Breyer M.D. Annu. Rev. Pharmacol. Toxicol. 41 (2001) 661
14. Krall J.F., Barrett J.D., Jamgotchian N., and Korenman S.G.J. Endocrinology 102 (1984) 329
15. Chen M.C.Y., Amirian D.A., Toomey M., Sanders M.J., and Soll A.H. Gastroenterology 94 (1988) 1121
16. Ushikubi F., Segi E., Sugimoto Y., Murata T., Matsuoka T., Kobayashi T., Hizaki H., Tuboi K., Katsuyama M., Ichikawa A., Tanaka T., Yoshida N., and Narumiya S. Nature 395 (1998) 281
17. McCafferty G.P., Misajet B.A., Laping N.J., Edwards R.M., and Thorneloe K.S. Am. J. Physiol. Renal Physiol. 295 (2008) 507
18. Su X., Lashinger E.R.S., Leon L.A., Hoffman B.E., Hieble J.P., Gardner S.D., Fries H.E., Edwards R.M., Li J., and Laping N.J. Am. J. Physiol. Renal Physiol. 295 (2008) 585
19. Su X., Leon L.A., Wu C.W., Morrow D.M., Jaworski J.-P., Hieble J.P., Lashinger E.S.R., Jin J., Edwards R.M., and Laping N.J. Am. J. Physiol. Renal Physiol. 295 (2008) 984
20. Shimazaki Y., Kameo K., Tanami T., Tanaka H., Ono N., Kiuchi Y., Okamoto S., Sato F., and Ichikawa A. Bioorg. Med. Chem. 8 (2000) 353
21. Collins P.W. J. Med. Chem. 29 (1986) 437
22. Juteau H., Gareau Y., Labelle M., Sturino C.F., Sawyer N., Tremblay N., Lamontagne S., Carriere M.C., Denis D., and Metters K.M. Bioorg. Med. Chem. 9 (2001) 1977
23. 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., and Labelle M. Bioorg. Med. Chem. Lett. 12 (2002) 2583
24. 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., and Metters K.M. Bioorg. Med. Chem. Lett. 16 (2006) 5639
25. Zegar S., Tokar C., Enache L.A., Rajagopol V., Zeller W., O'Connell M., Singh J., Muellner F.W., and Zembower D.E. Org. Process Res. Dev. (2007) 747
26. Zhou N., Zeller W., Krohn M., Anderson H., Zhang J., Onua E., Kiselyov A.S., Ramirez J., Halldorsdottir G., Andersson P., Gurney M.E., and Singh J. Bioorg. Med. Chem. Lett. 19 (2009) 123
27. Functional activity was determined by measuring mobilization of intracellular calcium on a fluorimetric imaging plate reader (FLIPR) as described in detail in Ref. 10c.
28. Zeng, Q.; Yao, G.; Wohlhieter, G. E.; Viswanadhan, V. N.; Tasker, A.; Rider, J. T.; Monenschein, H.; Dominguez, C.; Bourbeau, M. P. WO Patent 2006044860-A2, 2006; Chem Abstr. 2004, 144, 432820.
29. For synthesis of methyl-1,4-benzoxazine-6-carboxylate, see:. Walker D.P., Wishka D.G., Piotrowski D.W., Jia S., Reitz S.C., Yates K.M., Myers J.K., Vetman T.N., Margolis B.J., Jacobsen E.J., Acker B.A., Groppi V.E., Wolfe M.L., Thornburgh B.A., Tinholt P.M., Cortes-Burgos L.A., Walters R.R., Hester M.R., Seest E.P., Dolak L.A., Han F., Olson B.A., Fitzgerald L., Staton B.A., Raub T.J., Hajos M., Hoffmann W.E., Li K.S., Higdon N.R., Wall T.M., Hurst R.S., Wong E.H.F., and Rogers B.N. Bioorg. Med. Chem. 14 (2006) 8219 Further elaboration to the N-ethylbenzoxazine-6-carboxylic acid was completed using standard alkylation conditions: NaH (6 mol equiv), iodoethane (6 mol equiv) in 1 M THF at 80 °C for 18 h, followed by hydrolysis of the crude alkylation product (4 mol equiv NaOH in MeOH at 80 °C) to afford the desired carboxylic acid for synthesis of compound 24
30. Selectivity screening for compound 24 was conducted using radioligand binding assays for the hEP1, hEP2, hEP4, and hTP receptors as detailed in Ref. 9. Binding studies for the hFP receptor were completed by Cerep (Redmond, WA). COX1 and COX2 inhibition was measured using human whole blood in ELISA assay format as described in detail in the following references:. Warner T.D., Giuliano F., Vojnovic I., Bukasa A., Mitchell J.A., and Vane J.R. Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 7563
31. Patrignani P., Panara M.R., Greco A., Fusco O., Natoli C., Iacobelli S., Cipollone F., Ganci A., Creminon C., Maclouf J., and Patrono C. J. Pharmacol. Exp. Ther. 271 (1994) 1705