Bioactive hydroxyethylene dipeptide isosteres with hydrophobic (P3- P1)-moieties. A novel strategy towards small non-peptide renin inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 13, 1996, Pages 1589-1594

  Rasetti, Vittorio ^a   Cohen, N Claude ^a   Rüeger, Heinrich ^a   Göschke, Richard ^a   Maibaum, Jürgen ^a   Cumin, Frederic ^a   Fuhrer, Walter ^a   Wood, Jeanette M ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOTENSIN 2 RECEPTOR ANTAGONIST; CGP 38560; RENIN INHIBITOR;

ARTICLE; BLOOD PRESSURE REGULATION; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROPHOBICITY; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION;

EID: 0030576323     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00279-X     Document Type: Article

References (44)

1. 1. (a) Sealey, J.E.; Laragh, J.M. Hypertension: Pathophysiology, Diagnosis and Management; Laragh, J.M.; Brenner, B.M., Eds.; Raven Press, New York, 1995; pp 1763-1796.
2. (b) Waeber, B.; Nussberger, J.; Brunner, H.R. Hypertension: Pathophysiology, Diagnosis and Management; Laragh, J.M.; Brenner, B.M., Eds.; Raven Press, New York, 1995; pp 2861-2876.
3. (c) Timmermans, P.B.M.W.M.; Wong, P.C.; Chiu, A.T.; Herblin, W.F.; Benfield, P.; Carini, D.J.; Lee, R.L.; Wexler, R.R.; Saye, J.A.M.; Smith, R.D. Pharmacological Reviews 1993, 45, 205-251.
4. 2. For reviews:(a) Kleinert, H.D. Exp. Opin. Invest. Drugs 1994, 3, 1087-1104.
5. (b) Greenlee, W. J. Med.Res.Rev. 1990,10, 173-236.
6. 3. (a) Kleinert, H.D.; Rosenberg, S.H.; Baker, W.R.; Stein, H.H.; Klinghofer, V.; Barlow, J.; Spina, K.; Polakowski, J.; Kovar, P.; Cohen, J.; Denissen, J. Science 1992, 257, 1940-1943.
7. (b) Rosenberg, S.H.; Spina, K.P.; Condon, S.L.; Polakowski, J.S.; Yao, Z.; Kovar, P.; Stein, H.H.; Cohen, J.; Barlow, J.L.; Klinghofer, V.; Egan, D.A.; Tricarico, K.A.; Perun, T.J.; Baker, W.R.; Kleinen, H.D. J. Med. Chem. 1993, 36, 460-467.
8. 4. Bühlmayer, P.; Caselli, A.; Fuhrer, W.; Göschke, R.; Rasetti, V.; Rüeger, H.; Stanton, J. L.; Criscione, L.; Wood, J. M. J. Med. Chem. 1988, 31, 1839-1846.
9. 5. Cohen, N.C. Trends in Med. Chem. '88; van der Goot, H.; Dománi, G.; Pallos, L.; Timmerman, H., Eds.; Elsevier Science Publishers: Amsterdam, 1989; pp. 13-28.
10. 6. Sibanda, B.L.; Blundell, T.L.; Hobart, P.M.; Fogliano, M.; Bindra, J.S.; Dominy, B.W.; Chirgwin, J.M. FEBS Letters 1984, 174, 102-111.
11. 7. Rahuel, J.; Priestle, J.P.; Grütter, M.G. J. Struct. Biol. 1991, 107, 227-236.
12. 8. Atsuumi, S.; Nakano, M.; Koike, Y.; Tanaka, S.; Matsuyama, K.; Nakano, M.; Morishima, H. Chem. Pharm. Bull. 1992, 40, 364.
13. 9. Luly, J.R.; Bolis, G.; BaMaung, N.; Soderquist, J.; Dellaria, J.; Stein, H.; Cohen, J.; Perun, T.J.; Greer, J.; Plattner, J.J. J. Med. Chem. 1988, 31, 532-539.
14. 10. (a) Rasetti, V.; Rüeger, H.; Cohen, N.C.; Göschke, R.; Browne, L.J. Swiss Chem. Soc. Autumn Meeting, Bern (Switzerland), Oct. 1989;
15. (b) Brotherton-Pleiss, C.E.; Newman, L.D.; Waterbury, L.D.; Schwartzberg, M.S. Peptides: Chemistry and Biology; 12th Am. Pept. Symp., Cambridge Mass. USA 1991; Smith, J. A.; Rivier, J. E., Eds.; Escom Science:Leiden, 1992; pp.816-817.
16. 11. Szewczuk, Z.; Rebholz, K.L.; Rich, D.H. Int. J. Peptide Protein Res. 1992, 40, 233-242.
17. 12. (a) Harris, C.J.; Arrowsmith, R.J.; Davies, D.E.; Morton, J.A.; Allan, G.; Dann, J.G. The Renin Angiotensin System as a Therapeutic Target; Basel, Switzerland; Abstracts of the Meeting October 29th-31st 1989, p. 39.
18. (b) Cooper, J.B.; Foundling, S.I.; Blundell, T.L.; Arrowsmith, R.J.; Harris, C.J.; Champness, J.N. Topics in Med. Chem., 4th SCI-RSC Med. Chem. Symp. Cambridge, Engl. 1987; Leeming, P. R., Ed.; Royal Society of Chemistry Special Publication, No. 65; pp. 308-313.
19. 13. (a) Plummer, M.; Hamby, J.M.; Hingorani, G.; Batley, B.L.; Rapundalo, S.T. Bioorg. Med. Chem. Lett. 1994, 3, 2119-2124.
20. 1 bridging ligands in the design of HIV-1 protease inhibitors, see: Romeo, S.; Houseman, K.; Mueller, R.A.; Rich, D.H. MEDI 54, 205th ACS National Meeting, Denver, Co., March 28-April 2, 1993.
21. 1 bridging ligands in the design of HIV-1 protease inhibitors, see: Romeo, S.; Houseman, K.; Mueller, R.A.; Rich, D.H. MEDI 54, 205th ACS National Meeting, Denver, Co., March 28-April 2, 1993.
22. 14. Lefker, B.A.; Hada, W.A.; Wright, A.S.; Martin, W.H.; Stock, I.A.; Schulte, G.K.; Pandit, J.; Danley, D.E.; Ammirati, M.J.; Sneddon, S.F. Bioorg. Med. Chem. Lett. 1995, 5, 2623-2626.
23. 15. For a related account based on our design efforts, see: Hanessian, S.; Raghavan, S. Bioorg. Med. Chem. Lett. 1994, 4, 1697-1702.
24. 16. Sali, A.; Veerapandian, B.; Cooper, J.B.; Foundling, S.I.; Hoover, D.J.; Blundell, T.L. The EMBO J. 1989, 8, 2179-2188.
25. 17. Boger, J.; Payne, L.S.; Perlow, D.S.; Lohr, N.S.; Poe, M.; Blaine, E.H.; Ulm, E.H.; Schorn, T.W.; LaMont, B.I.; Lin, T.-Y.; Kawai, M.; Rich, D.H.; Veber, D.F. J. Med. Chem. 1985, 28, 1779-1790.
26. 18. (a) Holladay, M.W.; Rich, D.H. Tetrahedron Letters 1983, 4401-4404.
27. (b) For analogues of compound 33 see: Holladay, M.W.; Salituro, F.S.; Rich, D.H. J.Med.Chem. 1987, 30, 374-383.
28. 19. (a) Schöllkopf, U. Tetrahedron 1983, 2085.
29. (b) Schöllkopf, U. Pure Appl. Chem. 1983, 1799-1806.
30. 1H-NMR and/or FAB mass spectrometry.
31. 6).
32. 22. (a) Skita, A.; Rössler, R. Ber.Dtsch.Chem.Ges. 1939, 72, 265-272.
33. (b) Berglund, R.A.; Braish, T.F.; Jakubowski, J.A.; Fuchs, P.L. Bioorg. Med. Chem. Lett. 1991, 1, 649-652.
34. (c) Kleschick, W.A. J.Org.Chem. 1986, 51, 5429-5433.
35. (d) For the starting material of 21b, see: Wood, H.C.S.; Stirling, I. US Patent, US3963719.
36. 3, see: Martin, S.F.; Austin, R.E.; Oalmann, C.J.; Baker, W.R.; Condon, S.L.; deLara, E.; Rosenberg, S.H.; Spina, K.P.; Stein, H.H.; Cohen, J.; Kleinert, H.D. J. Med. Chem. 1992, 35, 1710-1721.
37. 24. Heck, R.F. Acc. Chem. Res. 1979, 12, 146-151. For a recent review, see: Meijere, F.E.; Meyer, F.E. Angew. Chem. 1994, 106, 2473-2506; for couplings of vinylglycine derivatives, see: Crisp, J.T.; Glink, P.T. Tetrahedron 1992, 48, 3541-3556.
38. 24. Heck, R.F. Acc. Chem. Res. 1979, 12, 146-151. For a recent review, see: Meijere, F.E.; Meyer, F.E. Angew. Chem. 1994, 106, 2473-2506; for couplings of vinylglycine derivatives, see: Crisp, J.T.; Glink, P.T. Tetrahedron 1992, 48, 3541-3556.
39. 24. Heck, R.F. Acc. Chem. Res. 1979, 12, 146-151. For a recent review, see: Meijere, F.E.; Meyer, F.E. Angew. Chem. 1994, 106, 2473-2506; for couplings of vinylglycine derivatives, see: Crisp, J.T.; Glink, P.T. Tetrahedron 1992, 48, 3541-3556.
40. 25. Prepared from rac-6and 2(R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (cf. Ref. [20]) in 3 steps (62 % yield).
41. 26. (a) Kempf, D.J. J.Org.Chem. 1986, 51, 3921-3926.
42. 1H-NMR of isomers; Göschke, R. et al.; manuscript in preparation. The isomer of 30f prepared from the more polar 4(R)-29 was inactive in the enzyme binding assay.
43. 3 amide bond of peptide inhibitors and residue 219 (threonine or serine; numbering refers to renin) of renin and other aspartyl proteases are commonly observed in enzyme inhibitor complexes: see for example Ref. [8].
44. 3 moiety has led to a pronounced enhancement of binding affinity in other series of small molecule renin inhibitors. These results will be reported elsewhere. (Received in Belgium 12 April 1996; accepted 10 June 1996)