Discovery of VTP-27999, an alkyl amine renin inhibitor with potential for clinical utility

ACS Medicinal Chemistry Letters

Volumn 2, Issue 10, 2011, Pages 747-751

  Jia, Lanqi ^a   Simpson, Robert D ^a   Yuan, Jing ^a   Xu, Zhenrong ^a   Zhao, Wei ^a   Cacatian, Salvacion ^a   Tice, Colin M ^a   Guo, Joan ^a   Ishchenko, Alexey ^a   Singh, Suresh B ^a   Wu, Zhongren ^a   McKeever, Brian M ^a   Bukhtiyarov, Yuri ^a   Johnson, Judith A ^a   Doe, Christopher P ^b   Harrison, Richard K ^a   McGeehan, Gerard M ^a   Dillard, Lawrence W ^a   Baldwin, John J ^a   Claremon, David A ^a  

^a Vitae Pharmaceuticals   (United States)

^b GLAXOSMITHKLINE   (United States)

Author keywords

aspartyl protease; hypertension; Renin; structure based drug design

Indexed keywords

CYTOCHROME P450 3A4; RENIN; RENIN INHIBITOR; UNCLASSIFIED DRUG; VTP 27999;

ANIMAL CELL; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; HUMAN CELL; HYPERTENSION; IC 50; NONHUMAN; PRIORITY JOURNAL; RAT;

RATTUS;

EID: 80054732055     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml200137x     Document Type: Article

References (26)

1. Skeggs, L.; Kahn, J. R.; Lentz, K.; Shumway, N. P. Preparation, purification, and amino acid sequence of a polypeptide renin substrate J. Exp. Med. 1957, 106, 439-53
2. Remuzzi, G.; Perico, N.; Macia, M.; Ruggenenti, P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease Kidney Int. 2005, 99 (Suppl.) S57-S65
3. Ruiz-Ortega, M.; Ruperez, M.; Esteban, V.; Rodriguez-Vita, J.; Sanchez-Lopez, E.; Carvajal, G.; Egido, J. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases Nephrol., Dial., Transplant. 2006, 21, 16-20 (Pubitemid 43057101)
4. Bader, M.; Ganten, D. Update on tissue renin-angiotensin systems J. Mol. Med. 2008, 86, 615-621
5. Zaman, M. A.; Oparil, S.; Calhoun, D. A. Drugs targeting the renin-angiotensin-aldosterone system Nat. Rev. Drug Discovery 2002, 1, 621-636 (Pubitemid 37368827)
6. Wood, J. M.; Stanton, J. L.; Hofbauer, K. G. Inhibitors of renin as potential therapeutic agents J. Enzyme Inhib. 1987, 1, 169-85 (Pubitemid 17131778)
7. Samani, N. J.; Cumin, F.; Kelly, M.; Wood, J. M. Expression of components of the RAS during prolonged blockade at different levels in primates Am. J. Physiol. 1994, 267, E612-E619
8. Winearls, C. G. Chronic kidney disease: definition and staging-an orthodox view Clinical Med. 2009, 9, 563-4
9. Hollenberg, N. K. Direct renin inhibition and the kidney Nat. Rev. Nephrol. 2010, 6, 49-55
10. Mende, C. W. Application of Direct Renin Inhibition to Chronic Kidney Disease Cardiovasc. Drugs Ther. 2010, 24, 139-149
11. Greenlee, W. J. Renin Inhibitors Med. Res. Rev. 1990, 10, 173-36
12. Rosenberg, S. H. Renin Inhibitors. In Progess in Medicinal Chemistry; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier Science: 1995; Vol. 32, pp 37-114.
13. Tice, C. M.; McGeehan, G. M.; Claremon, D. A. Antihypertensives: Renin Inhibitors. In Burger's Medicinal Chemistry, Drug Discovery, and Development, 7 th ed.; Abraham, D. J.; Rotella, D. P., Eds.; Wiley: 2010; Vol. 4, pp 239-266.
14. Bezencon, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remen, L.; Sifferlen, T.; Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.; Delahaye, 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
15. Chen, A.; Dube, D.; Dube, L.; Gagne, S.; Gallant, M.; Gaudreault, M.; Grimm, E.; Houle, R.; Lacombe, P.; Laliberte, S.; Liu, S.; MacDonald, D.; Mackay, B.; Martin, D.; McKay, D.; Powell, D.; Levesque, J.-F. Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study Bioorg. Med. Chem. Lett. 2010, 20, 5074-5079
16. Scheiper, B.; Matter, H.; Steinhagen, H.; Stilz, U.; Böcskei, Z.; Fleury, V.; McCort, G. Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 6268-6272
17. Webb, R. L.; Schiering, N.; Sedrani, R.; Maibaum, J. Direct Renin Inhibitors as a New Therapy for Hypertension J. Med. Chem. 2010, 53, 7490-7520
18. Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Rahuel, J.; Baum, H. P.; Cohen, N. C.; Schnell, C. R.; Fuhrer, W.; Gruetter, 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 (Pubitemid 47525468)
19. Xu, Z.; Cacatian, S.; Yuan, J.; Simpson, R. D.; Jia, L.; Zhao, W.; Tice, C. M.; Flaherty, P. T.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; McKeever, B. M.; Scott, B. B.; Bukhtiyarov, Y.; Berbaum, J.; Mason, J.; Panemangalore, R.; Cappiello, M. G.; Bentley, R.; Doe, C. P.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. Optimization of orally bioavailable alkyl amine renin inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 694-699
20. Tice, C. M.; Xu, Z.; Yuan, J.; Simpson, R. D.; Cacatian, S. T.; Flaherty, P. T.; Zhao, W.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; Scott, B. B.; Bukhtiyarov, Y.; Berbaum, J.; Mason, J.; Panemangalore, R.; Cappiello, M. G.; Mueller, D.; Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A. Design and optimization of renin inhibitors: Orally bioavailable alkyl amines Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545
21. Williams, P. A.; Cosme, J.; Vinkovic, D. M.; Ward, A.; Angove, H. C.; Day, P. J.; Vonrhein, C.; Tickle, I. J.; Jhoti, H. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone Science 2004, 305, 683-686 (Pubitemid 39006760)
22. Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain Biochem. Biophys. Res. Commun. 1967, 27, 157-162
23. Cerep Delta Screen.
24. MDS Pharma Services Spectrum Screen.
25. Ganten, D.; Wagner, J.; Zeh, K.; Bader, M.; Michel, J. B.; Paul, M.; Zimmermann, F.; Ruf, P.; Hilgenfeldt, U.; Ganten, U. Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 7806-10
26. Gregg, R. E.; McGeehan, G. M.; Bryson, C. C.; Danser, A. H. J.; Claremon, D. A.; Balcarek, J. M. VTP-27999: A Novel Direct Renin Inhibitor with Potential for Superior Renal Protection in Diabetic Nephropathy. In American Diabetes Association: 71st Scientific Session, San Diego, CA, June 24-28, 2011.