Pyridine amides as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 11, 2008, Pages 3168-3172

  Wang, Haixia ^a   Ruan, Zheming ^a   Li, James J ^a   Simpkins, Ligaya M ^a   Smirk, Rebecca A ^a   Wu, Shung C ^a   Hutchins, Robert D ^a   Nirschl, David S ^a   Van Kirk, Katy ^a   Cooper, Christopher B ^a   Sutton, James C ^a   Ma, Zhengping ^a   Golla, Rajasree ^a   Seethala, Ramakrishna ^a   Salyan, Mary Ellen K ^a   Nayeem, Akbar ^a   Krystek Jr , Stanley R ^a   Sheriff, Steven ^a   Camac, Daniel M ^a   Morin, Paul E ^a   Carpenter, Brian ^a   Robl, Jeffrey A ^a   Zahler, Robert ^a   Gordon, David A ^a   Hamann, Lawrence G ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

11 HSD1; 11 Hydroxysteroid dehydrogenase type 1; Pyridine amide

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE; 11BETA HYDROXYSTEROID DEHYDROGENASE TYPE 1; AMIDE; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; PYRIDINE AMIDE DERIVATIVE;

ARTICLE; CRYSTAL STRUCTURE; IN VITRO STUDY; PROTEIN EXPRESSION; SYNTHESIS;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; AMIDES; COMBINATORIAL CHEMISTRY TECHNIQUES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 44249087617     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.04.069     Document Type: Article

References (28)

1. Tomlinson J.W., Walker E.A., Bujalska I.J., Draper N., Lavery G.G., Cooper M.S., Hewison M., and Stewart P.M. Endocrine Rev. 25 (2004) 831
2. Bujalska I.J., Kumar S., and Stewart P.M. Lancet 349 (1997) 1210
3. Ricketts M.L., Verhaeg J.M., Bujalska I., Howie A.J., Rainey W.E., and Stewart P.M. J. Clin. Endocrinol. Metab. 83 (1998) 1325
4. Brereton P.S., van Driel R.R., Suhaimi F., Koyama K., Dilley R., and Krozowski Z. Endocrinology 142 (2001) 1644
5. Whorwood C.B., Mason J.I., Ricketts M.L., Howie A.J., and Stewart P.M. Mol. Cell. Endocrinol. 110 (1995) R7
6. Jellinck P.H., Pavlides C., Sakai R.R., and McEwen B.S. J. Steroid. Biochem. Mol. Biol. 71 (1999) 139
7. Moisan M.P., Seckl J.R., and Edwards C.R.W. Endocrinology 127 (1990) 1450
8. Andrews R.C., Rooyackers O., and Walker B.R. J. Clin. Endocrinol. Metab. 88 (2003) 285
9. Alberts P., Nilsson C., Selen G., Engblom L.O.M., Edling N.H.M., Norling S., Klingstrom G., Larsson C., Forsgren M., Ashkzari M., Nilsson C.E., Fiedler M., Bergqvist E., Ohman B., Bjorkstrand E., and Abrahmsen L.B. Endocrinology 144 (2003) 4755
10. Kotelevtsev Y., Holmes M.C., Burchell A., Houston P.M., Schmoll D., Jamieson P., Best R., Brown R., Edwards C.R.W., Seckl J.R., and Mullins J.J. Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 14924
11. Morton N.M., Holmes M.C., Fievet C., Staels B., Tailleux A., Mullins J.J., and Seckl J.R. J. Biol. Chem. 276 (2001) 41293
12. Masuzaki H., Paterson J., Shinyama H., Morton N.M., Mullins J.J., Seckl J.R., and Flier J.S. Science 294 (2001) 2166
13. Masuzaki H., Yamamoto H., Kenyon C.J., Elmquist J.K., Morton N.M., Paterson J.M., Shinyama H., Sharp M.G.F., Fleming S., Mullins J.J., Seckl J.R., and Flier J.S. J. Clin. Invest. 112 (2003) 83
14. Kotelevtsev Y.V., Brown R.W., Fleming S., Kenyon C., Edwards C.R.W., Seckl J.R., and Mullins J.J. J. Clin. Invest. 103 (1999) 683
15. Barf T., Vallgarda J., Emond R., Haggstrom C., Kurz G., Nygren A., Larwood V., Mosialou E., Axelsson K., Olsson R., Engblom L., Edling N., Ronquist-Nii Y., Ohman B., Alberts P., and Abrahmsen L. J. Med. Chem. 45 (2002) 3813
16. Xiang J., Ipek M., Suri V., Tam M., Xing Y., Huang N., Zhang Y., Tobin J., Mansour T., and McKew J. Bioorg. Med. Chem. 15 (2007) 4396
17. Rohde J.J., Pliushchev M.A., Sorensen B.K., Wodka D., Shuai Q., Wang J., Fung S., Monzon K.M., Chiou W.J., Pan L., Deng X., Chovan L.E., Ramaiya A., Mullaly M., Henry R.F., Stolarik D.F., Imade H.M., Marsh K.C., Beno D.W.A., Fey T.A., Droz B.A., Brune M.E., Camp H.S., Sham H.L., Frevert E.U., Jacobson P.B., and Link J.T. J. Med. Chem. 50 (2007) 149
18. Sorensen B., Winn M., Rohde J., Shuai Q., Wang J., Fung S., Monzon K., Chiou W., Stolarik D., Imade H., Pan L., Deng X., Chovan L., Longenecker K., Judge R., Qin W., Brune M., Camp H., Frevert E.U., Jacobson P., and Link J.T. Bioorg. Med. Chem. Lett. 17 (2007) 527
19. Patel J.R., Shuai Q., Dinges J., Winn M., Pliushchev M., Fung S., Monzon K., Chiou W., Wang J., Pan L., Wagaw S., Engstrom K., Kerdesky F.A., Longenecker K., Judge R., Qin W., Imade H.M., Stolarik D., Beno D.W.A., Brune M., Chovan L.E., Sham H.L., Jacobson P., and Link J.T. Bioorg. Med. Chem. Lett. 17 (2007) 750
20. Yeh V., Kurukulasuriya R., Madar D., Patel J., Fung S., Monzon K., Chiou W., Wang J., Jacobson P., Sham H., and Link J. Bioorg. Med. Chem. Lett. 16 (2006) 5408
21. Schuster D., Maurer E., Laggner C., Nashev L., Wilckens T., Langer T., and Odermatt A. J. Med. Chem. 49 (2006) 3454
22. Gu X., Dragovic J., Koo G.C., Koprak S.L., LeGrand C., Mundt S.S., Shah K., Springer M., Tan E., Thieringer R., Hermanowski-Vosatka A., Zokian H., Balkovec J., and Waddell S.T. Bioorg. Med. Chem. Lett. 15 (2005) 5266
23. Olson S., Aster S.D., Brown K., Carbin L., Graham D., Hermanowski-Vosatka A., LeGrand C., Mundt S., Robbins M., Schaeffer J., Slossberg L., Szymonifka M., Thieringer R., Wright S., and Balkovec J. Bioorg. Med. Chem. Lett. 15 (2005) 4359
24. Coppola G., Kukkola P., Stanton J., Neubert A., Marcopulos N., Bilci N., Wang H., Tomaselle H., Tan J., Aicher T., Knorr D., Jeng A., Dardik B., and Chatelain R. J. Med. Chem. 48 (2005) 6696
25. 50 < 100 nM) were counter-screened in an in vitro 11β-HSD2 assay. Human in vitro 11β-HSD2 activity was assayed by incubating cortisol (100 nM) and NAD (1 μM) with human 11β-HSD2 microsomes and measuring the product cortisone formed in the reaction by LC/MS/MS analysis. None of the compounds in this series showed significant inhibition of 11β-HSD2 at 10 μM.
26. Kluge R., Schulz M., and Liebsch S. Tetrahedron 52 (1996) 5773
27. PDB Deposition number is 3CH6. The dimethylpiperidinyl moiety also interacts with the side chains of Ile121, Tyr183, Val227, and the nicotinamide moiety of NADP. The central pyridinyl moiety interacts with Tyr177 side chain and the main chain in the vicinity of Gly216 and Leu217. Besides Tyr177, the 3-fluoro-4-methylphenyl moiety interacts with the side chains of Leu126, Met179, Val231, and Tyr284 from the other chain of the 11β-HSD1 dimer.
28. DeLano, W. L. The PyMol Molecular graphics System (2002), DeLano Scientific, San Carlos, CA, US. http:/www.pymol.org.