Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 8, 2011, Pages 2554-2558

  Griebenow, Nils ^a   Flessner, Timo ^a   Buchmueller, Anja ^a   Raabe, Martin ^b   Bischoff, Hilmar ^a   Kolkhof, Peter ^a  

^a BAYER PHARMA AG   (Germany)

^b Cardiology Research ^*

Author keywords

3 Benzazepin 2 ones; Atherosclerosis; Inhibitor; SAR; Squalene synthase

Indexed keywords

SQUALENE SYNTHASE INHIBITOR; TETRAHYDRO 2H 3 BENZAZEPIN 2 ONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; ATHEROSCLEROSIS; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HYPERLIPIDEMIA; STRUCTURE ACTIVITY RELATION;

ANIMALS; BENZAZEPINES; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; HUMANS; MICE; MICROSOMES, LIVER; MOLECULAR CONFORMATION; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79953288885     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.02.004     Document Type: Article

References (25)

1. K.I. Carpender, S.E. Taylor, J.A. Ballantine, B. Fussell, B. Halliwell, and M.J. Mitchinson Biochim. Biophys. Acta 1167 1993 121
2. A.J. Brown, E.L. Mander, I.C. Gelissen, L. Kritharides, R.T. Dean, and W. Jessup J. Lipid Res. 41 2000 226
3. A.P. Kourounakis, C. Charitos, E.A. Rekka, and P.N. Kourounakis J. Med. Chem. 51 2008 5861
4. T. Walley, P. Folino-Gallo, P. Stephens, and E. Van Ganse Br. J. Clin. Pharmacol. 60 2005 543
5. J. Burnett Curr. Opin. Investig. Drugs 7 2006 850
6. S. Seiki, and W.H. Frishman Cardiol. Rev. 17 2009 70
7. 3H]-farnesyl pyrophosphate and incubated for 10 min at 37 °C. Subsequently, 100 μl solution was extracted with 200 μl chloroform, 200 μl methanol and 60 μl 5 N sodium hydroxide and adjusted to 2 mM squalene. An aliquot of the organic phase was mixed with scintillation fluid and measured for beta-emission.
8. T. Miki, M. Kori, A. Fujishima, H. Mabuchi, R. Tozawa, M. Nakamura, Y. Sugiyama, and H. Yukimasa Bioorg. Med. Chem. 10 2002 385
9. T. Miki, M. Kori, H. Mabuchi, H. Banno, R. Tozawa, M. Nakamura, S. Itokawa, Y. Sugiyama, and H. Yukimasa Bioorg. Med. Chem. 10 2002 401
10. For experimental details and characterization of the compounds see: Griebenow, N.; Flessner, T.; Raabe, M.; Bischoff, H. Ger. Offen. DE 102004006325, 2005.
11. K.F. Schmidt Angew. Chem. 36 1923 511 524
12. K.F. Schmidt Chem. Ber. 57 1924 704
13. 4 = N‴-tert-butyl-N,N′,N″- tris[tris(dimethylamino)phosphoranylidene]phosphorimidic triamide.
14. R. Schwesinger, and H. Schlemper Angew. Chem., Int. Ed. Engl. 26 1987 1167
15. 1H NMR.
16. C.A. Busacca, and R.E. Johnson Tetrahedron Lett. 33 1992 165
17. G. Tóth, and K.E. Kövér Synth. Commun. 25 1995 3067
18. G. Simchen, and W. Krämerer Chem. Ber. 102 1969 3656
19. McDonald, I. M.; Dunstone, D. J. PCT Int. Appl., WO 2006051312, 2006.
20. J.S. Yadav, B.V.S. Reddy, M.S. Reddy, and A.R. Prasad Tetrahedron Lett. 43 2002 9703
21. T. Satoh, S. Suzuki, Y. Suzuki, Y. Miyaji, and Z. Imai Tetrahedron Lett. 52 1969 4555
22. 5b.
23. 14C]-mevalonolactone. One hour after mevalonolactone application, livers were removed and the amount of hepatic cholesterol synthesis was determined by sterol extraction.
24. 4.
25. After po administration of 3 mg/kg (37: 47% reduction, lapaquistat: 73% reduction).