Design and synthesis of potent, selective inhibitors of endothelin- converting enzyme

Journal of Medicinal Chemistry

Volumn 41, Issue 9, 1998, Pages 1513-1523

  Wallace, Eli M ^a,b   Moliterni, John A ^a   Moskal, Michael A ^a   Neubert, Alan D ^a   Marcopulos, Nicholas ^a   Stamford, Lisa B ^a   Trapani, Angelo J ^a   Savage, Paula ^a   Chou, Mary ^a   Jeng, Arco Y ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [[5 (2 FLUOROPHENYL) 2 [(PHOSPHONOMETHYL)AMINO]PENT 4 YNOYL]AMINO] 4 METHYLPENTANOIC ACID; 2 [[5 (3 FLUOROPHENYL) 2 [(PHOSPHONOMETHYL)AMINO]PENT 4 YNOYL]AMINO] 4 METHYLPENTANOIC ACID; 3 CYCLOHEXYL 2 [[5 (2,4 DIFLUOROPHENYL) 2 [(PHOSPHONOMETHYL)AMINO]PENT 4 YNOYL]AMINO]PROPIONIC ACID; [[1 [(2 BIPHENYL 4 YLETHYL) CARBAMOYL] 4 (2 FLUOROPHENYL)BUT 3 YNYL]AMINO]METHYL]PHOSPHONIC ACID; ENDOTHELIN 1; ENDOTHELIN CONVERTING ENZYME; MEMBRANE METALLOENDOPEPTIDASE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; ENZYME ASSAY; ENZYME INHIBITION; ENZYME SYNTHESIS; PROTEIN PROCESSING;

ACETYLENE; AMINO ACID SEQUENCE; ANIMALS; ASPARTIC ENDOPEPTIDASES; BLOOD PRESSURE; CHO CELLS; CRICETINAE; DRUG DESIGN; ENDOTHELIN-1; ENZYME INHIBITORS; HUMANS; MALE; METALLOENDOPEPTIDASES; MOLECULAR SEQUENCE DATA; NEPRILYSIN; PHOSPHONIC ACIDS; RATS; RATS, SPRAGUE-DAWLEY; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 15644384509     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970787c     Document Type: Article

References (37)

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7. Phosphoramidon (1), an NEP inhibitor with moderate ECE-1 inhibitory activity, has shown positive effects in several cardiovascular disease models: (a) Schultz, S. C.; Grady, B.; Cole, F.; Hamilton, I.; Burhop, K.; Malcolm, D. S. A Role for Endothelin and Nitric Oxide in the Pressor Response to Diaspirin Cross-Linked Hemoglobin. J. Lab. Clin. Med. 1993, 122, 301-308. (b) McMahon, E. G.; Palomo, M. A.; Moore, W. M. Phosphoramidon Blocks the Pressor Activity of Big Endothelin (1-39) and Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmacol. 1991, 17 (Suppl. 7), S29-S33. (c) Vemulapalli, S.; Watkins, R. W.; Brown, A.; Cook, J.; Bernardino, V.; Chiu, P. J. S. Disparate Effects of Phosphoramidon on Blood Pressure in SHR and DOCA-salt Hypertensive Rats. Life Sci. 1993, 53, 783-793. (d) Grover, G. J.; Sleph, P. G.; Fox, M.; Trippodo, N. C. Role of Endothelin-1 and Big Endothelin-1 in Modulating Coronary Vascular Tone, Contractile Function and Severity of Ischemia in Rat Hearts. J. Pharmacol. Exp. Ther. 1992, 263, 1074-1082. (e) Vemulapalli, S.; Chiu, P. J. S.; Chintala, M.; Bernardio, V. Attenuation of Ischemic Acute Renal Failure by Phosphoramidon in Rats. Pharmacology 1993, 47, 188-193. (f) Matsumura, Y.; Ikegawa, R.; Suzuki, Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.; Watanabe, M.; Morimoto, S. Phosphoramidon Prevents Cerebral Vasospasm Following Subarachnoid Hemorrhage in Dogs: The Relationship to Endothelin-1 Levels in the Cerebrospinal Fluid. Life Sci. 1991, 49, 841-848.
8. Phosphoramidon (1), an NEP inhibitor with moderate ECE-1 inhibitory activity, has shown positive effects in several cardiovascular disease models: (a) Schultz, S. C.; Grady, B.; Cole, F.; Hamilton, I.; Burhop, K.; Malcolm, D. S. A Role for Endothelin and Nitric Oxide in the Pressor Response to Diaspirin Cross-Linked Hemoglobin. J. Lab. Clin. Med. 1993, 122, 301-308. (b) McMahon, E. G.; Palomo, M. A.; Moore, W. M. Phosphoramidon Blocks the Pressor Activity of Big Endothelin (1-39) and Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmacol. 1991, 17 (Suppl. 7), S29-S33. (c) Vemulapalli, S.; Watkins, R. W.; Brown, A.; Cook, J.; Bernardino, V.; Chiu, P. J. S. Disparate Effects of Phosphoramidon on Blood Pressure in SHR and DOCA-salt Hypertensive Rats. Life Sci. 1993, 53, 783-793. (d) Grover, G. J.; Sleph, P. G.; Fox, M.; Trippodo, N. C. Role of Endothelin-1 and Big Endothelin-1 in Modulating Coronary Vascular Tone, Contractile Function and Severity of Ischemia in Rat Hearts. J. Pharmacol. Exp. Ther. 1992, 263, 1074-1082. (e) Vemulapalli, S.; Chiu, P. J. S.; Chintala, M.; Bernardio, V. Attenuation of Ischemic Acute Renal Failure by Phosphoramidon in Rats. Pharmacology 1993, 47, 188-193. (f) Matsumura, Y.; Ikegawa, R.; Suzuki, Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.; Watanabe, M.; Morimoto, S. Phosphoramidon Prevents Cerebral Vasospasm Following Subarachnoid Hemorrhage in Dogs: The Relationship to Endothelin-1 Levels in the Cerebrospinal Fluid. Life Sci. 1991, 49, 841-848.
9. Phosphoramidon (1), an NEP inhibitor with moderate ECE-1 inhibitory activity, has shown positive effects in several cardiovascular disease models: (a) Schultz, S. C.; Grady, B.; Cole, F.; Hamilton, I.; Burhop, K.; Malcolm, D. S. A Role for Endothelin and Nitric Oxide in the Pressor Response to Diaspirin Cross-Linked Hemoglobin. J. Lab. Clin. Med. 1993, 122, 301-308. (b) McMahon, E. G.; Palomo, M. A.; Moore, W. M. Phosphoramidon Blocks the Pressor Activity of Big Endothelin (1-39) and Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmacol. 1991, 17 (Suppl. 7), S29-S33. (c) Vemulapalli, S.; Watkins, R. W.; Brown, A.; Cook, J.; Bernardino, V.; Chiu, P. J. S. Disparate Effects of Phosphoramidon on Blood Pressure in SHR and DOCA-salt Hypertensive Rats. Life Sci. 1993, 53, 783-793. (d) Grover, G. J.; Sleph, P. G.; Fox, M.; Trippodo, N. C. Role of Endothelin-1 and Big Endothelin-1 in Modulating Coronary Vascular Tone, Contractile Function and Severity of Ischemia in Rat Hearts. J. Pharmacol. Exp. Ther. 1992, 263, 1074-1082. (e) Vemulapalli, S.; Chiu, P. J. S.; Chintala, M.; Bernardio, V. Attenuation of Ischemic Acute Renal Failure by Phosphoramidon in Rats. Pharmacology 1993, 47, 188-193. (f) Matsumura, Y.; Ikegawa, R.; Suzuki, Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.; Watanabe, M.; Morimoto, S. Phosphoramidon Prevents Cerebral Vasospasm Following Subarachnoid Hemorrhage in Dogs: The Relationship to Endothelin-1 Levels in the Cerebrospinal Fluid. Life Sci. 1991, 49, 841-848.
10. Phosphoramidon (1), an NEP inhibitor with moderate ECE-1 inhibitory activity, has shown positive effects in several cardiovascular disease models: (a) Schultz, S. C.; Grady, B.; Cole, F.; Hamilton, I.; Burhop, K.; Malcolm, D. S. A Role for Endothelin and Nitric Oxide in the Pressor Response to Diaspirin Cross-Linked Hemoglobin. J. Lab. Clin. Med. 1993, 122, 301-308. (b) McMahon, E. G.; Palomo, M. A.; Moore, W. M. Phosphoramidon Blocks the Pressor Activity of Big Endothelin (1-39) and Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmacol. 1991, 17 (Suppl. 7), S29-S33. (c) Vemulapalli, S.; Watkins, R. W.; Brown, A.; Cook, J.; Bernardino, V.; Chiu, P. J. S. Disparate Effects of Phosphoramidon on Blood Pressure in SHR and DOCA-salt Hypertensive Rats. Life Sci. 1993, 53, 783-793. (d) Grover, G. J.; Sleph, P. G.; Fox, M.; Trippodo, N. C. Role of Endothelin-1 and Big Endothelin-1 in Modulating Coronary Vascular Tone, Contractile Function and Severity of Ischemia in Rat Hearts. J. Pharmacol. Exp. Ther. 1992, 263, 1074-1082. (e) Vemulapalli, S.; Chiu, P. J. S.; Chintala, M.; Bernardio, V. Attenuation of Ischemic Acute Renal Failure by Phosphoramidon in Rats. Pharmacology 1993, 47, 188-193. (f) Matsumura, Y.; Ikegawa, R.; Suzuki, Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.; Watanabe, M.; Morimoto, S. Phosphoramidon Prevents Cerebral Vasospasm Following Subarachnoid Hemorrhage in Dogs: The Relationship to Endothelin-1 Levels in the Cerebrospinal Fluid. Life Sci. 1991, 49, 841-848.
11. Phosphoramidon (1), an NEP inhibitor with moderate ECE-1 inhibitory activity, has shown positive effects in several cardiovascular disease models: (a) Schultz, S. C.; Grady, B.; Cole, F.; Hamilton, I.; Burhop, K.; Malcolm, D. S. A Role for Endothelin and Nitric Oxide in the Pressor Response to Diaspirin Cross-Linked Hemoglobin. J. Lab. Clin. Med. 1993, 122, 301-308. (b) McMahon, E. G.; Palomo, M. A.; Moore, W. M. Phosphoramidon Blocks the Pressor Activity of Big Endothelin (1-39) and Lowers Blood Pressure in Spontaneously Hypertensive Rats. J. Cardiovasc. Pharmacol. 1991, 17 (Suppl. 7), S29-S33. (c) Vemulapalli, S.; Watkins, R. W.; Brown, A.; Cook, J.; Bernardino, V.; Chiu, P. J. S. Disparate Effects of Phosphoramidon on Blood Pressure in SHR and DOCA-salt Hypertensive Rats. Life Sci. 1993, 53, 783-793. (d) Grover, G. J.; Sleph, P. G.; Fox, M.; Trippodo, N. C. Role of Endothelin-1 and Big Endothelin-1 in Modulating Coronary Vascular Tone, Contractile Function and Severity of Ischemia in Rat Hearts. J. Pharmacol. Exp. Ther. 1992, 263, 1074-1082. (e) Vemulapalli, S.; Chiu, P. J. S.; Chintala, M.; Bernardio, V. Attenuation of Ischemic Acute Renal Failure by Phosphoramidon in Rats. Pharmacology 1993, 47, 188-193. (f) Matsumura, Y.; Ikegawa, R.; Suzuki, Y.; Takaoka, M.; Uchida, T.; Kido, H.; Shinyama, H.; Hayashi, K.; Watanabe, M.; Morimoto, S. Phosphoramidon Prevents Cerebral Vasospasm Following Subarachnoid Hemorrhage in Dogs: The Relationship to Endothelin-1 Levels in the Cerebrospinal Fluid. Life Sci. 1991, 49, 841-848.
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