The P1 N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4863-4867

  Yamaguchi, Yasuchika ^b   Menear, Keith ^a   Cohen, Nissim Claude ^c   Mah, Robert ^a   Cumin, Frédéric ^a   Schnell, Christian ^a   Wood, Jeanette M ^a   Maibaum, Jürgen ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NAGASAKI INTERNATIONAL UNIVERSITY   (Japan)

^c Synergix Ltd   (Israel)

Author keywords

Aliskiren analogues; Hydroxyethylene dipeptide isosters; RAAS, renin inhibitors; Renin angiotensin aldosterone system

Indexed keywords

ALISKIREN; ALISKIREN DERIVATIVE; BENZAMIDE DERIVATIVE; FUROSEMIDE; RENIN; RENIN INHIBITOR; UNCLASSIFIED DRUG; AMIDE; ANTIHYPERTENSIVE AGENT; ETHYLENE DERIVATIVE; FUMARIC ACID DERIVATIVE; HYDROXYETHYLENE; PROTEINASE INHIBITOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG POTENCY; ENZYME INHIBITION; HUMAN; IN VITRO STUDY; MARMOSET; NANOPHARMACEUTICS; NONHUMAN; PROTEIN MOTIF; ANIMAL; CALLITHRIX; CHEMISTRY; DRUG ANTAGONISM; METABOLISM; ORAL DRUG ADMINISTRATION; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; ANTIHYPERTENSIVE AGENTS; BENZAMIDES; CALLITHRIX; ETHYLENES; FUMARATES; HUMANS; PROTEASE INHIBITORS; RENIN; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 67651087348     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.128     Document Type: Article

References (36)

1. Rosamond W., Flegal K., Furie K., Go A., Greenlund K., Haase N., Hailpern S.M., Ho M., Howard V., Kissela B., Kittner S., Lloyd-Jones D., McDermott M., Meigs J., Moy C., Nichol G., O'Donnell C., Roger V., Sorlie P., Steinberger J., Thom T., Wilson M., and Hong Y. Circulation 117 (2008) e25
2. Nicholls M.G., and Robertson J.I.S. J. Hum. Hypertens. 14 (2000) 649
3. Azizi M., and Menard J. Circulation 109 (2004) 2492
4. Hershey J.C., Steiner B., Fischli W., and Feuerstein G. Drug Discovery Today: Therap. Strateg. 2 (2005) 181
5. Maibaum J.K., and Feldman D.L. Expert Opin. Ther. Patents 13 (2003) 589
6. Fisher N.D.L., and Hollenberg N.K. J. Am.Soc. Nephrol. 16 (2005) 592
7. Fisher N.D.L., and Hollenberg N.K. Exp. Opin. Invest. Drugs 10 (2001) 417
8. Danser A.H.J. J. Cardiovasc. Pharmacol. 50 (2007) 105
9. Yokokawa F., and Maibaum J. J. Expert Opin. Ther. Patents 18 (2008) 581
10. Rahuel J., Rasetti V., Maibaum J., Rueeger H., Goeschke R., Cohen N.-C., Stutz S., Cumin F., Fuhrer W., Wood J.M., and Gruetter M.G. Chem. Biol 7 (2000) 493
11. Goeschke R., Stutz S., Rasetti V., Cohen N.-C., Rahuel J., Rigollier P., Baum H.-P., Forgiarini P., Schnell C.R., Wagner T., Gruetter M.G., Fuhrer W., Schilling W., Cumin F., Wood J.M., and Maibaum J. J. Med. Chem. 50 (2007) 4818
12. Maibaum J., Stutz S., Goeschke 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., and Wood J.M. J. Med. Chem. 50 (2007) 4832
13. Wood J.M., Maibaum J., Rahuel J., Gruetter M.G., Cohen N.-C., Rasetti V., Rueger H., Goeschke R., Stutz S., Fuhrer W., Schilling W., Rigollier P., Yamaguchi Y., Cumin F., Baum H.-P., Schnell C.R., Herold P., Mah R., Jensen C., O'Brien E., Stanton A., and Bedigian M.P. Biochem. Biophys. Res. Commun. 308 (2003) 698
14. Jensen C., Herold P., and Brunner H.R. Nat. Rev. Drug Disc. 7 (2008) 399
15. Cohen N.C. Chem. Biol. Drug Des. 70 (2007) 557
16. The N-acyl-(hydroxyethyl)amine TSM isostere approach has been recently described for the inhibitor design targeting other aspartyl proteases. See for example:. Lee C.E., Kick E.K., and Ellman J.A. J. Am. Chem. Soc. 120 (1998) 9735
17. DeCamp A.E., Kawaguchi A.T., Volante R.P., and Shinkai I. Tetrahedron Lett. 32 (1991) 1867
18. Nakamura E., Sekiya K., and Kuwajima I. Tetrahedron Lett. 28 (1987) 337
19. Ochiai H., Nishihara T., Tamaru Y., and Yoshida Z. J. Org. Chem. 53 (1988) 1343
20. for related literature:. Kano S., Yokomatsu T., and Shibuya S. Tetrahedron Lett. 32 (1991) 233
21. 2 (130 mL) was added below -35 °C, and the mixture was stirred at -20 °C for 2 days. Standard workup afforded a 4:1 mixture of 5a/5b (27.7 g, 77%) as colorless oil.
22. + calcd 423.2854; found 423.2853.
23. For the preparation of other 3,4-disubstituted benzoic acid intermediates, see: Ehrhardt, C.; Irie, O.; Lorthiois, E. L. J.; Maibaum, J. K.; Ostermann, N.; Sellner, H. PCT Int. Appl. WO2006/100036(A1); Chem. Abstr. 2006, 145, 377192.
24. Knorr R., Trzeciak A., Bannwarth W., and Gillessen D. Tetrahedron Lett. 30 (1989) 1927
25. Goeschke R., Stutz S., Heinzelmann W., and Maibaum J. Helv. Chim. Acta 86 (2003) 2848
26. 2, -78 °C, 91%).
27. Enantiomeric purity of (3S,5S,1′R)-30 was determined by chiral HPLC using its (3R,5R,1′S)-enantiomer prepared from (R)-configured 27 according to Scheme 4.
28. Herold P., Duthaler R., Rihs G., and Angst C. J. Org. Chem. 54 (1989) 1178
29. Goeschke R., Cohen N.-C., Wood J.M., and Maibaum J. Bioorg. Med. Chem. Lett. 7 (1997) 2735
30. 11
31. 11 Human %PPB for 9, 34, 35 were not determined.
32. Maibaum, J.; Rasetti, V.; Rueeger, H.; Cohen, N.-C.; Goeschke, R.; Mah, R.; Rahuel, J.; Gruetter, M.; Cumin, F.; Wood, J. M. In Medicinal Chemistry: Today and Tomorrow, Proceedings of the AFMC International Medicinal Chemistry Symposium, Tokyo, Sept. 3-8, 1995, 1997, 155.
33. A recent patent application has disclosed related renin inhibitors including compounds 10 and 35: Miyazaki, S.; Nakamura, Y.; Nagayama, T.; Tokui, T. PTC Int. Appl. WO2007/148775(A1); Chem. Abstr. 2007, 148, 100512.
34. Schnell C.R., and Wood J.M. Am. J. Physiol. 264 (1993) H1509
35. 50 = 1 μM).
36. 2O, MeOH, rt, 7 h, 89%. (f) 4 N HCl-dioxane, rt, 69%.