A novel class of oral direct renin inhibitors: Highly potent 3,5-disubstituted piperidines bearing a tricyclic P3 - P1 pharmacophore

Journal of Medicinal Chemistry

Volumn 56, Issue 6, 2013, Pages 2196-2206

  Ostermann, Nils ^a   Ruedisser, Simon ^a   Ehrhardt, Claus ^a   Breitenstein, Werner ^a   Marzinzik, Andreas ^a   Jacoby, Edgar ^a   Vangrevelinghe, Eric ^a   Ottl, Johannes ^a   Klumpp, Martin ^a   Hartwieg, J Constanze D ^a   Cumin, Frederic ^a   Hassiepen, Ulrich ^a   Trappe, Jörg ^a   Sedrani, Richard ^a   Geisse, Sabine ^a   Gerhartz, Bernd ^a   Richert, Paul ^a   Francotte, Eric ^a   Wagner, Trixie ^a   Krömer, Markus ^a   Kosaka, Takatoshi ^b   Webb, Randy L ^b   Rigel, Dean F ^b   Maibaum, Jürgen ^a   Baeschlin, Daniel K ^a   more..

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PEPTIDOMIMETIC AGENT; PIPERIDINE DERIVATIVE; RENIN INHIBITOR;

ARTICLE; BLOOD PRESSURE; COMPUTER MODEL; CONTROLLED STUDY; DRUG BIOAVAILABILITY; ENZYMATIC ASSAY; ENZYME ACTIVE SITE; HYDROPHOBICITY; MOLECULAR DOCKING; MOLECULAR LIBRARY; MOLECULAR RECOGNITION; NUCLEAR MAGNETIC RESONANCE; PHARMACOPHORE; TRANSGENIC RAT; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG DESIGN; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; PIPERIDINES; PROTEASE INHIBITORS; PROTEIN CONFORMATION; RATS; RENIN;

EID: 84875712582     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301706j     Document Type: Article

References (25)

1. Kearney, P. M.; Whjelton, M.; Reynolds, K.; Muntner, P.; Whelton, P. K.; He, J. Global burden of hypertension: analysis of worldwide data Lancet 2005, 365, 217-223
2. Rosamond, W.; Flegal, K.; Friday, G.; Furie, K.; Go, A.; Greenlund, K.; Haase, N.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lloyd-Jones, D.; McDermott, M.; Meigs, J.; Moy, C.; Nichol, G.; O'Donnell, Ch. J.; Roger, V.; Rumsfeld, J.; Sorlie, P.; Steinberger, J.; Thom, T.; Wasserthiel-Smoller, S.; Hong, Y. Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2007, 115, e69-e171
3. Scott, B. B.; McGeehan, G. M.; Harrison, R. R. Development of inhibitors of the aspartyl protease renin for the treatment of hypertension Curr. Protein Pept. Sci. 2006, 7, 241-254
4. Skeggs, L. T.; Kahn, J. R.; Lentz, K.; Shumway, N. P. The preparation, purification, and amino acid sequence of a polypeptide renin substrate J. Exp. Med. 1957, 106, 439-453
5. Ruddy, M. C. Unmet Needs in Managing Hypertension: Potential Role of Direct Renin Inhibition Postgrad. Med. J. 2010, 122, 203-212
6. Volpe, M.; Pontremoli, R.; Borghi, C. Direct renin inhibition: from pharmacological innovation to novel therapeutic High Blood Pressure Cardiovasc. Prev. 2011, 18, 93-105
7. Stanton, A.; Jensen, C.; Nussberger, J.; O'Brien, E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren Hypertension 2003, 42, 1137-1143
8. Oh, B.-H.; Mitchell, J.; Herron, J. R.; Chung, J.; Khan, M.; Keefe, D. L. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24 h blood pressure control in patients with hypertension J. Am. Coll. Cardiol. 2007, 49, 1157-1163
9. Webb, R.; Schiering, N.; Sedrani, R.; Maibaum, J. Direct Renin Inhibitors as a New Therapy for Hypertension J. Med. Chem. 2010, 50, 4832-4844
10. Tice, C. M.; Singh, S. B. Evolution of Diverse Classes of Renin Inhibitors through the Years. In Aspartic Acid Proteases as Therapeutic Targets; Methods and Principles in Medicinal Chemistry, Vol. 45; Ghosh, A. K.; Mannhold, R.; Kubinyi, H.; Folkers, G., Eds.; Wiley-VCH: Weinheim, Germany, 2010; pp 297-324.
11. Maibaum, J.; Stutz, S.; Göschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.; Fuhrer, W.; Grütter, M. G.; Schilling, W.; Wood, J. M. Structural modification of the P2′ position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl- octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets J. Med. Chem. 2007, 50, 4832-4844
12. Maibaum, J.; Feldman, D. L. Case history on Tekturna/Rasilez (aliskiren), a highly efficacious direct oral renin inhibitor as a new therapy for hypertension Annu. Rev. Med. Chem. 2009, 44, 105-127
13. Bursavich, M. G.; Rich, D. H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles J. Med. Chem. 2002, 45, 541-558
14. Märki, H. P.; Binggeli, A.; Bittner, B.; Bohner-Lang, V.; Breu, V.; Bur, D.; Coassolo, Ph.; Clozel, J. P.; D'Arcy, A.; Doebeli, H.; Fischli, W.; Funk, Ch.; Foricher, J.; Giller, T.; Grüninger, F.; Guenzi, A.; Güller, R.; Hartung, T.; Hirth, G.; Jenny, Ch.; Kansy, M.; Klinkhammer, U.; Lave, T.; Lohri, B.; Luft, F. C.; Mervaala, E. M.; Müller, D. N.; Müller, M.; Montavon, F.; Oefner, Ch.; Qiu, C.; Reichel, A.; Sanwald-Ducray, P.; Scalone, M.; Schleimer, M.; Schmid, R.; Stadler, H.; Treiber, A.; Valdenaire, O.; Vieira, E.; Waldmeier, P.; Wiegand-Chou, R.; Wilhelm, M.; Wostl, W.; Zell, M.; Zell, R. Piperidine renin inhibitors: from leads to drug candidates Farmaco 2001, 56, 21-27
15. Holsworth, D. D.; Cai, C.; Cheng, X.-M.; Cody, W. L.; Downing, D. M.; Erasga, N.; Lee, C.; Powell, N. A.; Edmunds, J. J.; Stier, M.; Jalaie, M.; Zhang, E.; McConnell, P.; Ryan, M. J.; Bryant, J.; Li, T.; Kasani, A.; Hall, E.; Subedi, R.; Rahim, M.; Maiti, S.. Ketopiperazine-based renin inhibitors: optimization of the "C" ring Bioorg. Med. Chem. Lett. 2006, 16 (9) 2500-2504
16. Bezencon, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remeň, L.; Sifferlen, T.; Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.; Delahye, S.; Treiber, A.; Strickner, P.; Binkert, C.; Hess, P.; Steiner, B.; Fischli, W. Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors J. Med. Chem. 2009, 52, 3689-3702
17. Jia, L.; Simpson, R. D.; Yuan, J.; Xu, Z.; Zhao, W.; Cacatian, S.; Tice, C. M.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; McKeever, B. M.; Bukhtiyarov, Y.; Johnson, Judith, A.; Doe, C. P.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. Discovery of VTP-27999, An Alkyl Amine Renin Inhibitor with Potential for Clinical Utility ACS Med. Chem. Lett. 2011, 2, 747-751
18. Lorthiois, E.; Breitenstein, W.; Cumin, F.; Ehrhardt, C.; Francotte, E.; Jacoby, E.; Ostermann, N.; Sellner, H.; Takatoshi, K.; Webb, R.; Rigel, D.; Hassiepen, U.; Richert, P.; Wagner, T.; Maibaum, J. The Discovery of Novel Potent trans -3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches. J. Med. Chem. 2013, 56, DOI: 10.1021/jm3017078.
19. Ruedisser, S.; Ehrhardt, C.; Sedrani, R.; Maibaum, J. Unpublished results.
20. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and Validation of a Genetic Algorithm for Flexible Docking J. Mol. Biol. 1997, 267, 727-748
21. Cscore; Tripos Inc.: 1699 South Hanley Rd, St. Louis, Missouri, 63144, USA.
22. Jacoby, E.; Rüeger, H.; Breitenstein, W.; Marzinzik, A. Unpublished results.
23. 1′ residues, see: Atsuumi, S.; Nakano, M.; Koike, Y.; Tanaka, S.; Matsuyama, K.; Nakano, M.; Morishima, H. Renin inhibitors. I. Synthesis and structure-activity relationships of transition-state inhibitors containing homostatine analogs at the scissile bond Chem. Pharm. Bull. 1992, 40, 364-370
24. Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist's guide to molecular interactions J. Med. Chem. 2010, 53, 5061-5084
25. Bohlender, J.; Fukamizu, A.; Lippoldt, A.; Nomura, T.; Dietz, R.; Menard, J.; Murakami, K.; Luft, F. C.; Ganten, D. High human hypertension in transgenic rats Hypertension 1997, 29, 428-434