Identification and optimization of substituted 5-aminopyrazoles as potent and selective adenosine A1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 19, 2010, Pages 5891-5894

  Griebenow, Nils ^a   Bärfacker, Lars ^a   Meier, Heinrich ^a   Schneider, Dirk ^a   Teusch, Nicole ^a   Lustig, Klemens ^a   Kast, Raimund ^a   Kolkhof, Peter ^a  

^a BAYER PHARMA AG   (Germany)

Author keywords

5 Aminopyrazole; Adenosin A1 receptor antagonist; Diuresis; Heart failure; Natriuresis

Indexed keywords

5 AMINOPYRAZOLE; ADENOSINE A1 RECEPTOR ANTAGONIST; AMINOPYRAZOLE; HYDRAZINE; N ARYL AMINO PYRAZOLE; PYRAZOLE DERIVATIVE; ROLOFYLLINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; ARYLATION; CONTROLLED STUDY; DIURESIS; DRUG GLUCURONIDATION; DRUG IDENTIFICATION; HYDROXYLATION; IC 50; IN VIVO STUDY; NONHUMAN; PROCESS OPTIMIZATION; RAT; VALIDATION STUDY;

ADENOSINE A1 RECEPTOR ANTAGONISTS; ANIMALS; PYRAZOLES; RATS; RATS, WISTAR; RECEPTOR, ADENOSINE A1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77957593139     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.095     Document Type: Article

References (22)

1. G.C. Francis Clin. J. Med. 73 2006 S8
2. D.E. Forman, J. Butler, Y. Wang, W.T. Abraham, C.M. O'Connor, S.S. Gottlieb, E. Loh, B.M. Massie, M.W. Rich, L.W. Stevenson, J.B. Young, and H.M. Krumholz J. Am. Coll. Cardiol. 43 2004 61
3. B.B. Fredholm, A.P. Ijzerman, K.A. Jacobson, K.-N. Klotz, and J. Linden Pharmacol. Rev. 53 2001 527
4. M.M. Dohadwala, and M.M. Givertz Cardiovasc. Ther. 26 2008 276
5. Rudolph, J.; Cantin, L.-D.; Magnuson, S.; Bullock, W.; Bullion, A.-M.; Chen, L.; Chuang, C.-Y.; Liang, S.; Majumdar, D.; Ogutu, H.; Olague, A.; Qi, N.; Wickens, P. L. PCT Int. Appl., WO 2004050650, 2004.
6. Hobbs, R. E. Current Advances in Heart Disease, Proceedings of the World Congress on Heart Disease, 14th International Academy of Cardiology Annual Scientific Sessions, Toronto, ON, Canada, July 26-29, 2008, 273-276.
7. S.A. Doggrell Curr. Opin. Invest. Drugs 6 2005 962
8. For experimental details and characterization of the compounds see: (a) Baerfacker, L.; Kast, R.; Griebenow, N.; Meier, H.; Kolkhof, P.; Albrecht-Kuepper, B.; Nitsche, A., Stasch, J.-P.; Schneider, D.; Teusch, N.; Rudolph, J.; Whelan, J.; Bullock, W.; Pleasic-Williams, S. PCT Int. Appl., WO 2010020363, 2010.
9. Baerfacker, L.; Kast, R.; Griebenow, N.; Meier, H.; Kolkhof, P.; Albrecht-Kuepper, B.; Nitsche, A.; Stasch, J.-P.; Schneider, D.; Teusch, N. PCT Int. Appl., WO 2010020366, 2010.
10. Baerfacker, L.; Kast, R.; Griebenow, N.; Meier, H.; Kolkhof, P.; Albrecht-Kuepper, B.; Nitsche, A.; Stasch, J.-P.; Schneider, D.; Teusch, N. Ger. Offen. DE 102008039083, 2010.
11. Baerfacker, L.; Kast, R.; Griebenow, N.; Meier, H.; Kolkhof, P.; Albrecht-Kuepper, B.; Nitsche, A., Stasch, J.-P.; Schneider, D.; Teusch, N. Ger. Offen. DE 102008039082, 2010.
12. W. Chen, L.L. Koenigs, S.J. Thompson, R.M. Peter, A.E. Rettie, W.F. Trager, and S.D. Nelson Chem. Res. Toxicol. 11 1998 295
13. After seven days of acclimatization, male Wistar rats (body mass 200-350 g, Charles River Breeding or Harlan) were placed in metabolic cages (Tecniplast Deutschland GmbH, Hohenpeißenberg, Germany) on water ad libitum. The test compounds were administered either orally or intravenously in 1 ml/kg vehicle solution (40% PEG400 and 60% Tris buffer) to 6-8 animals per dosage group. The urine of the animals was collected at the bottom of the cages in special collecting tubes. The usual duration of urine collection was 4 h. The urine samples were analyzed for volume as well as sodium and potassium on a flame photometer.
14. B.D. Weatherley, G. Cotter, H.C. Dittrich, P. DeLucca, G.A. Mansoor, D.M. Bloomfield, P. Ponikowski, C.M. O'Connor, M. Metra, and B.M. Massie J. Card. Fail. 16 2010 25
15. Details on the design of PROTECT are available at http://www. clinicaltrials.gov, identifiers NCT00328692 and NCT00354458.
16. A global phase III trial began in August 2008; the trial was closed in December 2009. By March 2010, the drug was no longer listed on Biogen's pipeline and the program was presumed to have been discontinued.
17. Pronounced blood-brain-barrier penetration of KW-3902 has been found in rat (in house data).
18. Observations from clinical trials suggest that KW-3902 might lower the seizure threshold. See: M.M. Givertz, B.M. Massie, T.K. Fields, L.L. Pearson, and H.C. Dittrich J. Am. Coll. Cardiol. 50 2007 1551
19. M.M. Givertz Circ. Heart Fail. 2 2009 519
20. Inhouse data from MES and PTZ models. MES: maximal electroshock. PTZ: pentylenetetrazol.
21. J. Zablocki, E. Elzein, and R. Kalla Expert Opin. Ther. Patents 16 2006 1347
22. I. Giorgi, and P. Nieri Expert Opin. Ther. Patents 18 2008 677