The synthesis of aminobenzazepinones as anti-phenylalanine dipeptide mimics and their use in NEP inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 8, 1996, Pages 957-962

  Warshawsky, Alan M ^a   Flynn, Gary A ^a   Koehl, Jack R ^a   Mehdi, Shujaath ^a   Vaz, Roy J ^a  

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

BENZAZEPINE DERIVATIVE; ENZYME INHIBITOR; MDL 100192; MDL 100407; MDL 101628; MEMBRANE METALLOENDOPEPTIDASE; UNCLASSIFIED DRUG;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0029969518     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00149-7     Document Type: Article

References (17)

1. Ponder, J. W.; Richards, F. M. J. Mol. Biol. 1987, 193, 775. In the protein structures surveyed, the frequencies of occurrence for the gauche(-), anti, and gauche(+) conformers of phenylalanine was 53%:25%:21%, respectively.
2. Roques, B. P.; Noble, F.; Dauge, V.; Fournie-Zaluski, M. C.; Beaumont, A. Pharmacological Reviews 1993, 45, 87.
3. a) Flynn, G. A.; Burkholder, T. P.; Huber, E. W.; Bey, P. Bioorg. Med. Chem. Lett. 1991, 1, 309.
4. b) For other examples of 4-aminobenzazepinones as anti-Phe dipeptide mimics see: de Laszlo, S. E.; Bush, B.L.; Doyle, J. J.; Greenlee, W. J.; Hangauer, D. G.; Halgren, T. A.; Lynch, R. J.; Schorn, T. W.; Siegl, P. K. S. J. Med. Chem. 1992, 35, 833; and Tourwe, D.; Verschueren, K.; Van Binst, G.; Davis, P.; Porreca, F.; Hruby, V. J. Bioorg. Med. Chem. Lett. 1992, 2, 1305.
5. b) For other examples of 4-aminobenzazepinones as anti-Phe dipeptide mimics see: de Laszlo, S. E.; Bush, B.L.; Doyle, J. J.; Greenlee, W. J.; Hangauer, D. G.; Halgren, T. A.; Lynch, R. J.; Schorn, T. W.; Siegl, P. K. S. J. Med. Chem. 1992, 35, 833; and Tourwe, D.; Verschueren, K.; Van Binst, G.; Davis, P.; Porreca, F.; Hruby, V. J. Bioorg. Med. Chem. Lett. 1992, 2, 1305.
6. c) A related approach to anti-PheGly dipeptide mimics is described in Robl, J. A.; Simpkins, L. M.; Sulsky, R.; Sieber-McMaster, E.; Stevenson, J.; Kelley; Y. F.; Sun, C-Q; Misra, R. N.; Ryono, D. E.; Asaad, M. M.; Bird, J. E.; Trippodo, N. C.; Karanewsky, D. S Bioorg. Med. Chem. Lett. 1994, 4, 1795 and in Karanewsky, D. S.; Barrish, J. C; Petrillo, E. W.,Jr.; Robl, J. A.; Ryono, D. E. European Patent Application 0 599 444 A1, June 1, 1994.
7. c) A related approach to anti-PheGly dipeptide mimics is described in Robl, J. A.; Simpkins, L. M.; Sulsky, R.; Sieber-McMaster, E.; Stevenson, J.; Kelley; Y. F.; Sun, C-Q; Misra, R. N.; Ryono, D. E.; Asaad, M. M.; Bird, J. E.; Trippodo, N. C.; Karanewsky, D. S Bioorg. Med. Chem. Lett. 1994, 4, 1795 and in Karanewsky, D. S.; Barrish, J. C; Petrillo, E. W.,Jr.; Robl, J. A.; Ryono, D. E. European Patent Application 0 599 444 A1, June 1, 1994.
8. As in reference 2a, various conditions using triflic acid, trifluoroacetic acid, and trimethylsilyl triflate were examined.
9. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 6009.
10. 4) was unsuccessful.
11. Collington, E. W.; Meyers, A. I. J. Org. Chem. 1971, 36, 3044.
12. Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664.
13. Burkholder, T. P.; Huber, E. W.; Flynn, G. A. Bioorg. Med. Chem. Lett. 1993, 2, 231.
14. An alternate binding model for mercaptoacetyl amide based NEP inhibitors has been proposed in which the mercaptoacetyl side chain rather than the anti-phenylalanine residue would interact with the S1' subsite: Delaney, N. G.; Barrish, J. C.; Neubeck, R.; Natarajan, S.; Cohen, M.; Rovnyak, G. C.; Huber, G.; Murugesan, N.; Girotra, R.; Sieber-McMaster, E.; Robl, J. A.; Asaad, M. M.; Cheung, H. S.; Bird, J. E.; Waldron, T.; Petrillo, E. W. Bioorg. Med. Chem. Lett. 1994, 4, 1783, (cf. reference 12).
15. i value for MDL 101,601, the unconstrained PheLeu analog of MDL 100,407. This observation points toward the enhanced metabolic stability that can be gained by using conformationally constrained peptide mimics.
16. Flynn, G. A.; Beight, D. W.; Mehdi, S.; Koehl, J. R.; Giroux, E. L.; French, J. F.; Hake, P. W.; Dage, R.C. J. Med. Chem. 1993, 36, 2420.
17. i values were measured by the protocol described in French, J. F.; Flynn, G. A.; Giroux, E. L.; Mehdi, S.; Anderson, B.; Beach, D. C.; Koehl, J .R.; Dage, R. C. J. Pharmacol. Exp. Therap. 1994, 268, 180.