Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1)

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 22, 2011, Pages 6693-6698

  Wu, Shung C ^a   Yoon, David ^a   Chin, Janice ^b   Van Kirk, Katy ^b   Seethala, Ramakrishna ^a   Golla, Rajasree ^a   He, Bin ^a   Harrity, Thomas ^a   Kunselman, Lori K ^a   Morgan, Nathan N ^a   Ponticiello, Randolph P ^a   Taylor, Joseph R ^a   Zebo, Rachel ^a   Harper, Timothy W ^a   Li, Wenying ^b   Wang, Mengmeng ^a   Zhang, Lisa ^a   Sleczka, Bogdan G ^b   Nayeem, Akbar ^a   Sheriff, Steven ^b   Camac, Daniel M ^b   Morin, Paul E ^b   Everlof, John G ^b   Li, Yi Xin ^a   Ferraro, Cheryl A ^b   Kieltyka, Kasia ^b   Shou, Wilson ^b   Vath, Marianne B ^b   Zvyaga, Tatyana A ^b   Gordon, David A ^a   Robl, Jeffrey A ^a   more..

^a BRISTOL MYERS SQUIBB RESEARCH AND DEVELOPMENT   (United States)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

11 HSD1; Cross species activity; Hydroxyisoquinolines; Inhibitors; Type 2 diabetes

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; 2 CYANOPYRIDIN 3 YL GROUP; 3 HYDROXY 4 CYANOISOQUINOLINE; HYDROXYTETRAHYDROISOQUINOLINE; ISOQUINOLINE DERIVATIVE; PYRIMIDINOL; UNCLASSIFIED DRUG;

ARTICLE; DRUG IDENTIFICATION; HUMAN; METABOLIC PARAMETERS; MOUSE; NONHUMAN; PROCESS OPTIMIZATION;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ANIMALS; CELL LINE; DIABETES MELLITUS, TYPE 2; ENZYME INHIBITORS; HUMANS; ISOQUINOLINES; MICE; MICE, INBRED BALB C; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80054766392     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.09.058     Document Type: Article

References (27)

1. S. Wild, G. Roglic, A. Green, R. Sicree, and H. King Diabetes Care 27 2004 1047
2. M.-E. Patti, and S. Corvera Endocrine Rev. 31 2010 364 and references cited therein
3. J.W. Tomlinson, and P.M. Stewart Nat. Clin. Pract. Endocrinol. Metab. 1 2005 92
4. M. Wang Curr. Opin. Investig. Drugs 7 2006 319
5. E. Saiah Curr. Med. Chem. 15 2008 642
6. C.G. Schnackenberg Curr. Opin. Investig. Drugs 9 2008 295
7. C. Fotsch, and M. Wang J. Med. Chem. 51 2008 4851
8. P.M. Stewart, and J.W. Tomlinson Diabetes 58 2009 14
9. C.D. Boyle, and T.J. Kowalski Expert Opin. Ther. Pat. 19 2009 801
10. R. Ge, Y. Huang, G. Liang, and X. Li Curr. Med. Chem. 17 2010 412
11. A. Tiwari IDrugs 13 2010 266 and references cited therein
12. Y. Kotelevtsev, M.C. Holmes, A. Burchell, P.M. Houston, D. Schmoll, P. Jamieson, R. Best, R. Brown, C.R.W. Edwards, J.R. Seckl, and J. Mullins J. Proc. Natl. Acad. Sci. U.S.A. 94 1997 14924
13. N.M. Morton, M.C. Holmes, C. Fievet, B. Staels, A. Tailleux, J.J. Mullins, and J.R. Seckl J. Biol. Chem. 276 2001 41293
14. V.S.C. Yeh, R. Kurukulasuriya, S. Fung, K. Monzon, W. Chiou, J. Wang, D. Stolarik, H. Imade, R. Shapiro, V. Knourek-Segel, E. Bush, D. Wilcox, P.T. Nguyen, M. Brune, P. Jacobson, and J.T. Link Bioorg. Med. Chem. Lett. 16 2006 5555
15. J.R. Patel, Q. Shuai, J. Dinges, M. Winn, M. Pliushcher, S. Fung, K. Monzon, W. Chiou, J. Wang, L. Pan, S. Wagaw, K. Engstrom, F.A. Kerdesky, K. Longenecker, R. Judge, W. Qin, H.M. Imade, D. Stolarik, D.W.A. Beno, M. Brune, L.E. Chovan, H.L. Sham, and J.T. Link Bioorg. Med. Chem. Lett. 17 2007 750
16. L.D. Julian, Z. Wang, T. Bostick, S. Caille, R. Choi, M. DeGraffenreid, Y. Di, X. He, R.W. Hungate, J.C. Jaen, J. Liu, M. Monshouwer, D. McMinn, Y. Rew, A. Sundon, Sun, S. Daqing, H. Tu, S. Ursu, N. Walker, X. Yan, Q. Ye, and J.P. Power J. Med. Chem. 51 2008 3953
17. H. Cheng, J. Hoffman, P. Le, S.K. Nair, S. Cripps, J. Matthews, C. Smith, M. Yang, S. Kupchinsky, K. Dress, M. Edwards, B. Cole, E. Walters, C. Loh, J. Ermolieff, A. Fanjul, G.B. Bhat, J. Herrera, T. Pauly, N. Hosea, G. Paderes, and P. Rejto Bioorg. Med. Chem. Lett. 20 2010 2897
18. A.M. El-Khawaga, G.M. El-Naggar, K.M. Hassan, and A.M. El-Dean Phosphorus, Sulfur Silicon Relat. Elem. 44 1989 203
19. 50 value was then determined by amount of cortisol formed from a cortisol standard curve.
20. Vial containing sodium phosphate buffer (0.1 M, pH 7.2), test compound (30 μM), human liver microsome (2 mg/mL) and NADPH (2 mM) was incubated in a 37 °C water bath for 1 h. Ice cold acetonitrile was added to the incubation mixture. The mixture was centrifuged and the supernatant was analyzed with LC/MS/MS. Metabolites were identified based on the observed mass and UV spectra. Levels of metabolites were estimated based on UV peak area at 320-330 nm, assuming same extinction coefficient for metabolites and the parent.
21. A. McKillop, and D.P. Rao Synthesis 1977 760
22. Robl, J.A.; Wu, S.C.; Yoon, D., WO2008005910, 2008.
23. DIO mice were bled via tail tip in the fed state and dosed orally (7.5 ml/kg) with vehicle or drug (0.1% Tween 80, 0.5% methocel in water). At 30 min post dosing, mice were bled via tail tip and dosed orally (7.5 ml/kg) with DHC 10 mg/kg. All animals were bled at 30, 60 and 120 minutes post DHC dosing. 35 μL of whole blood were collected per time point in microvette tubes coated with EDTA and kept on ice. Samples were centrifuged at 40 °C for 10 min at 2500 RPM. Plasma corticosterone concentration was measured using EIA. AUC of corticosterone concentrations were calculated using Graphpad.
24. 1/2 was determined from the standard curve of the substrate concentration versus time.
25. A conformational search was first carry out for each compound to locate the global minimum energy conformation in aqueous phase using the OPLS 2005 force field with mixed-torsional low mode sampling using the Macromodel program. The RI-MP2 energy was calculated from the minimum-energy structure using the QChem package version 3.2.
26. 3. The N-methylated analog was prepared by the procedure described in A.R. Bassindale, D.J. Parker, P. Patel, and P.G. Taylor Tetrahedron Lett. 41 2000 4933
27. PDB Deposition number is 3TFQ.