Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors

Journal of Medicinal Chemistry

Volumn 40, Issue 4, 1997, Pages 495-505

  Ksander, Gary M ^a   De Jesus, Reynalda ^a   Yuan, Andrew ^a   Ghai, R D ^a   Trapani, A ^a   McMartin, Colin ^a,b   Bohacek, Regine ^a,c  

^a NOVARTIS PHARMA AG   (Switzerland)

^b Thistlesoft   (United States)

^c ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,3,4,5,6,7,8,9 OCTAHYDRO 2 MERCAPTO 3 OXO 1H 4 BENZAZACYCLOUNDECINE 5 CARBOXYLIC ACID; ATRIAL NATRIURETIC FACTOR; ENKEPHALINASE INHIBITOR; LACTAM DERIVATIVE; MACROCYCLIC COMPOUND; METALLOPROTEINASE INHIBITOR; PRODRUG; THERMOLYSIN; THIORPHAN; UNCLASSIFIED DRUG; ZINC;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG EFFECT; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME BINDING; ENZYME INHIBITION; ENZYME INHIBITOR COMPLEX; MOLECULAR MODEL; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT;

ANIMALS; ATRIAL NATRIURETIC FACTOR; BINDING SITES; DRUG SYNERGISM; LACTAMS; MODELS, CHEMICAL; MODELS, MOLECULAR; NEPRILYSIN; RATS; SOFTWARE; THIORPHAN;

EID: 0031047662     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960582o     Document Type: Article

References (36)

1. Winquist, R. J.; Hintze, T. H. Mechanisms of Atrial Natriuretic Factor-Induced Vasodilation. Pharmacol. Ther. 1990, 48, 417-426.
2. (b) Ruskoaho, H. Atrial Natriuretic Peptide: Synthesis, Release, and Metabolism. Pharmacol. Rev. 1992, 44, 479-602.
3. Tonolo, G.; Richards, A. M.; Manunta, P.; Pazzola, A.; Madeddu, P.; Towrie, R.; Fraser, R.; Glorioso, N. Low-Dose Infusion of Atrial Natriuretic Factor in Mild Essential Hypertension. Circulation 1989, 80, 893-902 and references cited therein.
4. (a) McMartin, C.; Hagen, M. E.; Sytwu, I.; Webb, R. L.; Wennogle, L. P.; Zimmerman, M. B. Degradation of Atrial Natriuretic Peptide (ANP): Effects of Endopeptidase EC. 24.11 Inhibition on Catabolism. FASEB J. 1988, 2, A936.
5. (b) Wennogle, L. P.; Ghai, R.; McMartin, C.; Webb, R. L.; Erion, M.; Gilligan, J.; Oei, H.; Zimmerman, M. B. Multiple Mechanisms Mediate Disappearance of ANF from the Vascular Compartment in the Rat. In Biol. Mol. Aspects Atrial Factors 1988, 13-27.
6. (c) Zimmerman, M. B.; McMartin, C. M.; Yasay, G.; Wennogle, L. P.; Webb, R. L. Degradation of Atrial Natriuretic Peptide: Pharmacologic Effects of Protease EC 24.11 Inhibition. FASEB J. 1988, 2, A937.
7. (d) Trapani, A. J.; Smits, G. J.; McGraw, D. E.; Spear, K. L.; Koepke, J. P.; Olins, G. M.; Blaine, E. H. Thiorphan, an Inhibitor of Endopeptidase 24.11, Potentiates the Natriuretic Activity of Atrial Natriuretic Peptide. J. Cardiovasc. Pharmacol. 1989, 14, 419-424.
8. (e) Webb, R. L.; Yasay, G. D.; McMartin, C.; McNeal, R. B.; Zimmerman, M. B. Degradation of Atrial Natriuretic Peptide: Pharmacologic Effects of Protease EC 24.11 Inhibition. J. Cardiovasc. Pharmacol. 1989, 14, 285-293
9. (f) Gros, C.; Souque, A.; Schwartz, J.-C. Inactivation of Atrial Natriuretic Factor in Mice in Vivo: Crucial Role of Enkephalinase (EC 3.4.24.11). Eur. J. Pharmacol. 1990, 179, 45-56.
10. (g) Toll, L.; Brandt, S. R.; Olsen, C. M.; Judd, A. K.; Almquist, R. G. Isolation and Characterization of a New Atrial Peptide-Degrading Enzyme from Bovine Kidney. Biochem. Biophys. Res. Commun. 1991, 175, 886-893.
11. (h) Vanneste, Y.; Pauwels, S.; Lambotte, L.; Michel, A.; Dimaline, R.; Deschodt-Lanckman, M. Respective Roles of Kallikrein and Endopeptidase 24.11 in the Metabolic Pathway of Atrial Natriuretic Peptide in the Rat. Biochem. J. 1990, 269, 801-806.
12. Roques, B. P.; Noble, F.; Daugé, V.; Fournier-Zaluski, M.-C.; Beaumont, A. Neutral Endopeptidase 24.11: Structure, Inhibition, and Experimental and Clinical Pharmacology. Pharmacol. Rev. 1993, 45, 87-146.
13. (a) Danilewicz, J. C.; Barclay, P. L.; Barnish, I. T.; Brown, S. F.; Campbell, S. F.; James, K.; Samuels, G. M. R.; Terrett, N. K.; Wythes, M. J. UK-69,578, a Novel Inhibitor of EC 3.4.24.11 which Increases Endogenous ANF Levels and Is Natriuretic and Diuretic. Biochem. Biophvs. Res. Commun. 1989, 164, 58-65.
14. (b) Erdos, E. G.; Skidgel, R. A. Neutral Endopeptidase 24.11 (Enkephalinase) and Regulators of Peptide Hormones. FASEB J. 1989, 3, 145-151.
15. (c) Gros, C.; Souque, A.; Schwartz, J.-C.; Duchier, J.; Cournot, A.; Baumer, P.; Lecomte, J.-M. Protection of Atrial Natriuretic Factor Against Degradation, Diuretic and Natriuretic Responses after Inhibition of Enkephalinase (EC 3.4.24.11). Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7580-7585.
16. (d) Haslanger, M. F.; Sybertz, E. J.; Neustadt, B. R.; Smith, E. M.; Nechuta, T. L.; Berger, J. Carboxyalkyl Dipeptides with Atrial Natriuretic Factor Potentiating and Antihypertensive Activity. J. Med. Chem. 1989, 32, 739-742.
17. (e) Sybertz, E. J.; Chiu, P. J. S.; Watkins, R. W.; Vemulapalli, S. Neutral Endopeptidase Inhibition: A Novel Means of Circulatory Modulation. J. Hypertension 1990, 8 (suppl. 7), S161-S167.
18. (f) Seymour, A. A.; Norman, J. A.; Asaad, M. M.; Fennell, S. A.; Swerdel, J. N.; Little, D. K.; Dorso, C. R. Renal and Depressor Effects of SQ 29,072, a Neutral Endopeptidase Inhibitor, in Conscious Hypertensive Rats. J. Cardiovasc. Pharmacol. 1990, 16, 163-172.
19. (g) Seymour, A. A.; Norman, J. A.; Asaad, M. M.; Fennell, S. A.; Little, D. K.; Kratunis, V. J.; Rogers, W. L. Antihypertensive and Renal Activity of SQ 28,603, an Inhibitor of Neutral Endopeptidase. J. Cardiovasc. Pharmacol. 1991, 17, 296-304.
20. MacPherson, L. J.; Bayburt, E. K.; Capparelli, M. P.; Bohacek, R. S.; Clarke, F. H.; Ghai, R. D.; Sakane, Y.; Berry, C. J.; Peppard, J. V.; Trapani, A. J. Design and Synthesis of an Orally Active Macrocyclic Netural Endopeptidase 24.11 Inhibitor. J. Med. Chem. 1993, 36, 3821-3828.
21. Stanton, J. L.; Sperbeck, D. M.; Trapani, A. J.; Cote, D.; Sakane, Y.; Berry, C. J.; Ghai, R. D. Heterocyclic lactam derivatives as dual angiotensin coverting enzyme and neutral endopeptidase 24.11 inhibitors. J. Med. Chem. 1993, 36, 3829-3833.
22. Matthews, B. W. Structural Basis of the Action of Thermolysin and Related Zinc Peptidases. Acc. Chem. Res. 1988, 21, 333-340.
23. Holland, D. R.; Karclay, P. L.; Danilewicz, J. C.; Matthews, B. W.; James, K. Inhibition of Thermolysin and Neutral Endopeptidase 24.11 by a Novel Glutaramide Derivative: X-ray Structure Determination of the Thermolysin-Inhibitor Complex. Biochemistry 1994, 33, 51-60.
24. Benchetrit, T.; Fournié-Zaluski, M. C.; Roques, B. P. Relationship Between the Inhibitory Potencies of Thiorphan and Retrothiorphan Enantiomers on Thermolysin and Neutral Endopeptidase 24.11 and their Interactions with the Thermolysin Acitve Site by Computer Modeling. Biochem. Biophys. Res. Commun. 1987, 147, 1034-1040.
25. Roques, B. P.; Lucas-Soroca, E.; Chaillet, P.; Costentin, J.; Fournié-Zaluski, M. Complete Differentiation Between Enkephalinase and Angiotensin-Converting Enzyme Inhibition by Retro-Thiorphan. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 3178-3182.
26. Bohacek, R. S.; Priestle, J.; Grutter, M. Unpublished results.
27. De Lombaert, S.; Erion, M. D.; Tan, J.; Blanchard, L.; El-Chehabi, L.; Ghai, R.; Sakane, Y.; Berry, C.; Trapani, A. J. N-Phosphonomethyl Dipeptides and Their Phophonate Prodrugs, a New Generation of Netural Endopeptidase (NEP, EC 3.4.24.11) Inhibitors. J. Med. Chem. 1994, 37, 498-511.
28. McMartin, C.; Bohacek, R. QXP; a basic set of powerful, user friendly computer routines for structue-based drug design. J. Comput.-Aided Mol. Des., in press.
29. Holden, H. M.; Tronrud, D. E.; Monzingo, A. F.; Weaver, L. H.; Matthews, B. W. Slow- and Fast-Binding Inhibitors of Thermolysin Display Different Modes of Binding: Crystallographic Analysis of Extended Phosphonamidate Transition-State Analogues. Biochemistry 1987, 26, 8542-8553.
30. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, T.; Shinamoucchi, T.; Tasumi, M. The Protein Data Bank: A Computer Based Archival File for Macromolecular Structures. J. Mol. Biol. 1977, 112, 535-542.
31. Abol, E. E.; Bernstein, F. C.; Bryant, S. H.; Koetzle, T. F.; Weng, J. In Cristallographic Databases-Information Content, Software Systems. Scientific Applications; Allen, F. H., Bergerhoff, G., Sievers, R., Eds.; Data Commission of the International Union of Crystallography: Bonn/Cambridge/Chester, 1987; pp 107-132.
32. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; G., C.; Chang, G.; Hendirckson, T.; Still, W. C. MACROMODEL - An Integrated Software System for Modelling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
33. Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. K. A New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Proteins. J. Am. Chem. Soc. 1984, 706, 765-784.
34. Guida, W. C.; Bohacek, R. S.; Erion, M. D. Probing the Conformational Space Available to Inhibitors in the Thermolysin Active Site Using Monte Carlo/Energy Minimization Techniques. J. Comput. Chem. 1992, 13, 214-228.
35. 1H NMR and the results obtained from an Ellmann SH test.
36. 8 However, because only the coordinates of thiorphan without those of thermolysin were released, Figure 2 shows thiorphan minimized in our thermolysin model. This conformation is almost identical to that from the crystal structure. The crystal structure of a close analog of the 10-membered macrocycle bound to thermolysin has also been determined (private communication, M. Gruetter). This structure agrees closely with our model of the 10-membered macrocycle shown in Figure 3.