Design and synthesis of novel, conformationally restricted HMG-CoA reductase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 16, 2007, Pages 4531-4537

  Pfefferkorn, Jeffrey A ^a   Choi, Chulho ^a   Song, Yuntao ^a   Trivedi, Bharat K ^a   Larsen, Scott D ^a   Askew, Valerie ^a   Dillon, Lisa ^a   Hanselman, Jeffrey C ^a   Lin, Zhiwu ^a   Lu, Gina ^a   Robertson, Andrew ^a   Sekerke, Catherine ^a   Auerbach, Bruce ^a   Pavlovsky, Alexander ^a   Harris, Melissa S ^a   Bainbridge, Graeme ^a   Caspers, Nicole ^a  

^a PFIZER INC   (United States)

Author keywords

HMG CoA reductase inhibitor; Hypercholesterolemia; Statin

Indexed keywords

CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; PYRROLE;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG BINDING; DRUG CONFORMATION; DRUG DESIGN; DRUG IDENTIFICATION; DRUG INHIBITION; DRUG POTENCY; DRUG SYNTHESIS; HYPERCHOLESTEROLEMIA; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PROTEIN SYNTHESIS; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHOLESTEROL; DRUG DESIGN; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERLIPIDEMIAS; MICE; MOLECULAR BIOLOGY; MOLECULAR STRUCTURE; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34447320746     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.05.097     Document Type: Article

References (24)

1. Grundy S.M. J. Intern. Med. 241 (1997) 295
2. Castelli W.P. Am. J. Med. 76 (1984) 4
3. For review, see:. Duriez P. Expert Opin. Pharmacother. 2 (2001) 1777
4. Grundy S.M., Cleeman J.I., Merz N.B., Brewer B., Clark L.T., Hunninghake D.B., Pasternak R.C., Smith S.C., and Stone N.J. Circulation 110 (2004) 227
5. Pfefferkorn, J. A.; Song, Y.; Sun, K.-L.; Miller, S. R.; Trivedi, B. K.; Choi, C.; Sorenson, R. J.; Bratton, L. D.; Unangst, P. C.; Larsen, S. D.; Poel, T.-J.; Cheng, X.-M.; Lee, C.; Erasga, N.; Auerbach, B.; Askew, V.; Dillon, L.; Hanselman, J. C.; Lin, Z.; Lu, G.; Robertson, A.; Olsen, K.; Mertz, T.; Sekerke, C.; Pavlovsky, A.; Harris, M. S.; Bainbridge, G.; Caspers, N.; Chen, H.; Eberstadt, M. Bioorg. Med. Chem. Lett. 2007, in press. doi:10.1016/j.bmcl.2007.05.097.
6. For a review of the X-ray structures of other inhibitors bound to HMG-CoA reductase, see:. Istvan E. Atheroscler. Suppl. 4 (2003) 3
7. Crystallization protocol and PDB coordinates for the X-ray structure in Figure 2 can be found in Ref. 5.
8. Additional evidence that such a conformational restriction might be successful was provided by the fact that the following N-methyl benzyl amide analog of compound 2 also demonstrated good potency against HMG-CoA reductase suggesting that N-alkylation necessary for installation of the conformational restriction would be tolerated: {A figure is presented}.
9. For a review of conformation restriction, see:. In: Hart P.A., Rich D.H., and Wermuth C.G. (Eds). The Practice of Medicinal Chemistry (1996), Academic Press, New York 393
10. For selected examples, see:. Bunch L., Liljefors T., Greenwood J.R., Frydenvang K., Brauner-Osborne H., Krogsgaard-Larsen P., and Madsen U. J. Org. Chem. 68 (2003) 1489
11. Graham J. Curr. Top. Med. Chem. 2 (2002) 903
12. Barton D.H.R., and Zard S.C. Chem. Commun. (1985) 1098
13. For additional experimental details on the synthesis of related compounds, see: Pfefferkorn, J. A.; Bowles, D. M.; Kissel, W.; Bolyles, D. C.; Choi, C.; Larsen, S. D.; Song, Y.; Sun, K.-L.; Miller, S.; Trivedi, B. K. Tetrahedron, in press.
14. Yang B.H., and Buchwald S.L. Org. Lett. 1 (1999) 35
15. Hamanaka N., Kosuge S., and Iguchi S. Synlett (1990) 139
16. Radl S. Syn. Comm. 33 (2003) 2275
17. Kambe S., and Yasuda H. Bull. Chem. Soc. Jpn. 41 (1968) 1441
18. Denmark S.E., and Marcin L.R. J. Org. Chem. 58 (1993) 3850
19. Gale P.A., Camiolo S., Tizzard G.J., Chapman C.P., Light M.E., Coles S.J., and Hursthouse M.B. J. Org. Chem. 66 (2001) 7849
20. Schürer S.C., and Blechert S. Sylett (1999) 1879
21. 50 values are reported as arithmetic mean for n ≥ 2 independent measurements unless otherwise noted. For detailed assay protocols, see: Bratton, L. D.; Auerbach, B.; Choi, C.; Dillon, L.; Hanselman, J. C.; Larsen, S. D.; Lu, G.; Olsen, K.; Pfefferkorn, J. A.; Robertson, A.; Sekerke, C.; Trivedi, B. K.; Unangst, P. C. Bioorg. Med. Chem. 2007, in press. doi:10.1016/j.bmc.2007.05.031.
22. As described in Ref. 5, in addition to in vitro potency and in vivo efficacy, an additional area of interest for HMG-CoA reductase inhibitors is selectivity for hepatocyte cells versus other cell types as this is thought to confer reduced risk of statin-induced mylagia. Given that analogs 41, 49, and 50 exhibited good hepatocyte activity, we also evaluated them for selectivity in a myocyte cell line (Ref. 5). Unfortunately, none of these compounds exhibited hepatoselectivity.
23. Hsiang B., Zhu Y., Wang Z., Wu Y., Sasseville V., Yang W.-P., and Kirchgessner T.G. J. Biol. Chem. 274 (1999) 37161
24. Coordinates for the X-ray structures in Figures 4 and 5 have been deposited at the PDB under filenames 2Q6B and 2Q6C, respectively.