Identification of a new biaryl scaffold generating potent renin inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 19, 2010, Pages 5822-5826

  Lacombe, Patrick ^a   Aspiotis, Renée ^a   Bayly, Christopher ^a   Chen, Austin ^a   Dubé, Daniel ^a   Fortin, Réjean ^a   Gallant, Michel ^a   Juteau, Hélne ^a   Liu, Suzanna ^a   McKay, Dan ^a   Roy, Patrick ^a   Wu, Tom ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

Anti hypertensive; Inhibitor; Renin

Indexed keywords

AMIDE; CYCLOPROPYLAMIDE; RENIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG IDENTIFICATION; DRUG INHIBITION; IC 50; IN VITRO STUDY; NONHUMAN; RAT; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; BIBENZYLS; ENZYME INHIBITORS; RATS; RENIN; STRUCTURE-ACTIVITY RELATIONSHIP;

RATTUS;

EID: 77957562386     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.127     Document Type: Article

References (20)

1. American Heart Association, Statistics, 2007
2. A. Ferro, R. Gilbert, and H. Krum Int. J. Clin. Pract. 60 2006 577
3. M.A. Weber Am. J. Hypertens. 5 1992 247S
4. M.E. Cooper Am. J. Hypertens. 17 2004 16S
5. K. Norris, and C. Vaughn Expert Rev. Cardiovasc. Ther. 1 2003 51
6. H. Cheng, and R.C. Harris Expert Opin. Drug Saf. 5 2006 631
7. E. O'Brien Expert Opin. Investig. Drugs 15 2006 1269
8. D.N. Muller, and F.C. Luft Clin. J. Am. Soc. Nephrol. 1 2006 221
9. M. Azizi, A.H. Gradman, and P.S. Sever J. R. A. A. System 10 2009 65
10. W.J. Greenlee Med. Res. Rev. 10 1990 173
11. S.H. Rosenberg Prog. Med. Chem. 32 1995 37
12. C.M. Tice Ann. Reports Med. Chem. 41 2006 155
13. D.L. Feldman, and J. Maibaum Ann. Reports Med. Chem. 44 2009 105
14. A. Chen, C. Bayly, O. Bezenon, S. Richard-Bildstein, D. Dubé, L. Dubé, S. Gagné, M. Gallant, M. Gaudreault, E. Grimm, R. Houle, P. Lacombe, S. Laliberté, J.-F. Lévesque, S. Liu, D. MacDonald, B. Mackay, D. Martin, D. McKay, D. Powell, L. Remec, S. Soisson, and S. Toulmond Bioorg. Med. Chem. Lett. 20 2010 2204
15. Superposition of AMBER ensemble average structures from 1000 ps NPT molecular dynamics calculations at 300 K with explicit solvent (TIP3P) and periodic boundary conditions. (Case et al. AMBER: AMBER8 D.A.; University of California: San Francisco, 2004, with extensive in-house small molecule parameters.)
16. Bayly, C. I.; Chen, A.C.; Dubé, D.; Dubé, L.; Gallant, M.; Lacombe, P.; MacDonald, D.; McKay, D.; Powell, D.A.; Grimm, E.L. WO-2007009250. 2007.
17. N. Miyaura, M. Murata, and T. Ishiyama J. Org. Chem. 60 1995 7508
18. 50 was determined by curve fitting software.
19. Citrate-plasma from human volunteers was pooled, aliquoted and stored frozen at -20 °C. Renin activity in pooled plasma was supplemented with recombinant human renin (150 pg/ml final concentration) in order to increase the readout of the assay. Five microliters of renin inhibitors, at various concentration in DMSO, was added to 80 μl of a mixture (7:1) of human plasma and a fast trapping primary AngI antibody (anti-AngI: AS1, bleed 6, pre-diluted 1:10 in horse serum) diluted initially 1:26.5 in assay buffer (PBS1X, 1 mM EDTA, 0.1% BSA, pH 7.4) and then diluted 1:3:3 in 3 M Tris, 200 mM EDTA, pH 7.2 (final anti-serum dilution 1:50,000) and was incubated at 37 °C for 2 h. As was done in the buffer assay, 12 μl of the renin reaction (or standards in the assay buffer) were measured for AngI accumulation by immunoassay.
20. D.D. Holsworth, M. Jalaie, T. Belliotti, C. Cai, W. Collard, S. Ferreira, N.A. Powell, M. Stier, E. Zhang, P. McConnell, I. Mochalkin, M.J. Ryan, J. Bryant, T. Li, A. Kasani, R. Subedi, S.N. Maiti, and J. Edmunds J. Bioorg. Med. Chem. Lett. 17 2007 3575