Substituted piperidines - Highly potent renin inhibitors due to induced fit adaptation of tile active site

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 10, 1999, Pages 1397-1402

  Vieira, Eric ^a   Binggeli, Alfred ^a   Breu, Volker ^a   Bur, Daniel ^a   Fischli, Walter ^b   Güller, Rolf ^c   Hirth, Georges ^a   Märki, Hans Peter ^a   Müller, Marcel ^a   Oefner, Christian ^a   Scalone, Michelangelo ^a   Stadler, Heinz ^a   Wilhelm, Maurice ^a   Wostl, Wolfgang ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b ACTELION PHARMACEUTICALS LTD   (Switzerland)

^c Chemspeed Ltd   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 CHLOROPHENYL) 3 (4 METHOXYBENZYL)PIPERIDINE; PIPERIDINE DERIVATIVE; REMIKIREN; RENIN INHIBITOR; UNCLASSIFIED DRUG;

ANTIHYPERTENSIVE ACTIVITY; ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; MOLECULAR INTERACTION; RACEMIC MIXTURE; REACTION ANALYSIS; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; STRUCTURE ACTIVITY RELATION;

BINDING SITES; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PIPERIDINES; RECOMBINANT PROTEINS; RENIN;

EID: 0033577692     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00195-X     Document Type: Article

References (24)

1. McGregor, G.A.; Markandu, N.D.; Roulston, J.E.; Jones, J.C.; Morton, J.J. Nature 1981, 291, 329-331.
2. Waeber, B.; Nussberger, J.; Brunner, H.R. in Handbook of Hypertension, Vol. 8: Pathophysiology of Hypertension - Regulatory Mechanisms; Zanchetti, A; Tarazi, R.C. (Eds), Elsevier Science Publishing Co, Amsterdam 1986; pp. 489-519.
3. Azizi, M.; Guyene, T.-T.; Chatellier, G.; Ménard, J. Journal of Hypertension 1994, 12, 419-427.
4. Neutel, J.M.; Luther, R.R.; Boger, R.S.; Weber, M.A. Am. Heart 1991, 122, 1094-1100.
5. Weber, M.A. Am. J. Hypertens. 1992, 5, 247S-251S.
6. Urata, H.; Healy, B.; Steweart, R.W.; Bumpus, F.M.; Husain, A. Circ. Res. 1990, 66, 883.
7. Wolny, A.; Clozel, J.P.; Rein, J.; Mory, P.; Vogt, P.; Turino, M.; Kiowski, W.; Fischli, W. Circulation Research 1997, 80, 219-227.
8. El Amrani, A.K.; Ménard, J.; Gonzales, M.F.; Michel, J.B. J. Cardiovasc. Pharmacol. 1993, 22, 231-239.
9. Hollenberg, N.K.; Fischer, N.D.L. Hypertension 1995, 26, 602-609.
10. van Paassen, P.; de Zeeuw, D.; de Jong, P. J. Cardiovasc. Pharmacol. 1995, 26, 39-45.
11. McMahon, S.; Cutler, J.A.; Stamler, J. Hypertension 1989,13(suppl. I), 145-150.
12. Kleinert, H.D. Cardiovasc. Drug Ther. 1995, 9, 645-655.
13. 2, 5%Pd/C, MeOH, r.t. (96%)). The absolute configuration of the chiral centers in positions 3 and 4 of the piperidine ring was determined by X-ray crystallographic analysis, and found to be (3S,4S) relative to the absolute (1S,4R) configuration of the camphanoyl moiety.
14. Oefner, C.; Binggeli, A.; Breu, V.; Bur, D.; Clozel, J.P.; D'Arcy, A.; Dorn, A.; Fischli, W.; Grüninger, F.; Güller, R.; Hirth, G.; Märki, H.P.; Mathews, S.; Müller, M.; Ridley, R.G.; Stadler, H.; Vieira, E.; Wilhelm, M.; Winkler, F.K.; Wostl, W. Chemistry&Biology 1999, 6, 127-131.
15. 50 values depicted are mean values of 2-5 independent determinations.
16. Michelot, D. Synthesis 1983, 130-134.
17. Hill, B.E.; Lythgoe, B.; Mirvish, S.; Trippett, S. J. Chem. Soc. 1955, 1770.
18. Hutchinson, D.W.; Thornton, D.M. Synthesis 1990, 135-137.
19. Nigam, S.C.; Mann, A.; Taddei, M.; Wermuth, G. Synth. Commun. 1989, 19, 3139-3142.
20. Mahboobi, S.; Bernauer, K. Helv. Chim. Acta 1988, 71, 2034.
21. Machin, P.J.; Hurst, D.N.; Bradshaw, R.M.; Blaber, L.C.; Burden, D.T. J. Med. Chem. 1983, 26, 1570-1576.
22. Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Tetrahedron 1983, 39, 169-174.
23. Single crystals of recombinant human renin complexed with (R,R)-39 were obtained and analysed as described (Ref. 14). They belong to the space group P4,2,2 with cell dimensions a=b=98.7 Å, c=95.9 Å, contain one molecule in the asymmetric unit and diffract to a resolution of about 3 Å. Coordinates of the refined structure will be deposited with the Brookhaven Data Bank.
24. Mathews, S.; Doebeli, H.; Pruschy, M.; Bosser, R.; D'Arcy, A.; Oefner, C.; Zulauf, M.; Gentz, R.; Breu, V.; Matile, H.; Schlaeger, J.; Fischli, W. Protein Expression and Purification 1996, 7, 81-91.