Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 21, 2005, Pages 4790-4793

  Dudash Jr , Joseph ^a   Zhang, Yongzheng ^a   Moore, John B ^a   Look, Richard ^a   Liang, Yin ^a   Beavers, Mary Pat ^a   Conway, Bruce R ^a   Rybczynski, Philip J ^a   Demarest, Keith T ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 ANILINOQUINOXALINONE; ANTIDIABETIC AGENT; ENZYME INHIBITOR; GLYCOGEN PHOSPHORYLASE INHIBITOR; QUINOXALINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHEMICAL BOND; CHEMICAL MODIFICATION; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; MOUSE; NONHUMAN; PHARMACOPHORE; RAT;

ANIMALS; BLOOD GLUCOSE; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; GLYCOGEN PHOSPHORYLASE; HYPOGLYCEMIC AGENTS; INHIBITORY CONCENTRATION 50; MICE; MICE, OBESE; QUINOXALINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 25144512037     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.07.021     Document Type: Article

References (18)

1. R.A. DeFronzo, R.C. Bonadonna, and E. Ferrannini Diabetes Care 15 1992 318
2. M.K. Hellerstein, R.A. Neese, P. Linfoot, M. Christiansen, S. Turner, and A. Letscher J. Clin. Invest. 100 1997 1305
3. W. Pimenta, N. Nurjhan, P.A. Jansson, M. Stumvoli, J. Gerich, and M. Korytkowski Diabetologia 37 1994 697
4. A.K. Ogawa, C.A. Willoughby, R. Bergeron, K.P. Ellsworth, W.M. Geissler, R.W. Myers, J. Yao, G. Harris, and K.T. Chapman Bioorg. Med. Chem. Lett. 13 2003 3405
5. DeFossa, E.; Kadereit, D.; Scoenafinger, K.; Klabunde, T.; Burger, H. J.; Herling, A.; Wendt, K. U.; Von Roedern, E.; Enhsen, A.; Rieke-Zapp, J. WO 03/084922; Chem. Abstr. 2003, 139, 323338.
6. DeFossa, E.; Kadereit, D.; Scoenafinger, K.; Klabunde, T.; Burger, H. J.; Herling, A.; Wendt, K. U.; Von Roedern, E.; Enhsen, A. WO 03/084923; Chem. Abstr. 2003, 139, 307602.
7. D.J. Hoover, S. Lefkowitz-Snow, J.L. Burgess-Henry, W.H. Martin, S.J. Armento, I.A. Stock, R.K. McPherson, P.E. Genereux, E.M. Gibbs, and J.L. Treadway J. Med. Chem. 41 1998 2934
8. A three dimensional pharmacophore was derived from a known GPa inhibitor, CP-91149. 3D searches were carried out against a multiconformer version of the corporate database using the Catalyst software available from Accelrys, Inc., (www.accelrys.com ). Compounds with desirable ADME (absorption, distribution, metabolism, and excretion) properties were subsequently selected from the original Catalyst electronic hit list by calculating ADME descriptors with the MOE software (available from The Chemical Computing Group, 1010 Sherbrooke Street West, Suite 910, Montreal, Canada H#A 2R7). The final list of compounds was tested and afforded compound 1 as one of the confirmed hits.
9. Enzyme inhibitory activity was determined using glycogen phosphorylase from rabbit muscle (Sigma P1261) by the method of Martin et al. W.H. Martin, D.J. Hoover, S.J. Armento, I.A. Stock, R.K. McPherson, D.F. Danley, R.W. Stevenson, E.J. Barrett, and J.L. Treadway Proc. Natl. Acad. Sci. U.S.A. 95 1998 1776
10. 1H NMR, LCMS) and were homogeneous by TLC.
11. S. Lavieri, and J.A. Zoltewicz J. Org. Chem. 66 2001 7227 and references cited therein
12. A. Basha, M. Lipton, and S.M. Weinreb Tetrahedron Lett. 48 1977 4171
13. W.C. Lumma, R.D. Hartman, W.S. Saari, E.L. Engelhardt, V.J. Lotti, and C.A. Stone J. Med. Chem. 24 1981 93
14. 14C]glucose for overnight incorporation into glycogen. The next day, unincorporated radioactivity is removed and cells are treated with test compound with or without.1 nM glucagon for 2 h. Cellular glycogen is collected by potassium hydroxide solubilization of the cells followed by ethanol extraction and the radioactivity determined. Glycogen breakdown is determined by comparing reduction of radioactivity from cells at time 0 versus time 2 h and inhibition of this breakdown by test compounds assessed.
15. 0 is the concentration of the dosing solution in M. C r final is the cumulative receiver concentration in M at the end of the incubation period. C d final is the concentration of the donor in Mat the end of the incubation period.
16. Tests were conducted at Absorption Systems, Exton, PA. Incubation at 37°C with test compound at 5 μM and 1 mg protein/mL human liver microsomal prep. Half life was determined by measuring the percent parent compound remaining. In this system, values above 30 min were considered acceptable.
17. Tests were conducted at Absorption Systems, Exton, PA. Equilibrium solubility was measured in pH 2.0 and pH 7.4 aqueous buffers. At least 1 mg of powder was combined with 1 mL of buffer to make ≥1 mg/mL mixture. These samples were shaken for ≥2 h and left to stand overnight at room temperature. The samples were then filtered through a 0.45-μm Nylon syringe filter that was first saturated with the sample. The filtrate was sampled twice, consecutively. All samples were assayed by LC/MS using electrospray ionization.
18. ob/ob Jackson Labs, Bar Harbor, ME) were at 6-7 weeks of age when received. Upon arrival, they were quarantined for 5 days, housed two mice per cage and given access to water and food ad libitum. Next, these mice were grouped based on their blood glucose levels. They were then given either vehicle (0.5% methycellulose), or compound (suspended in 0.5% methycellulose) at 30 mg/kg body weight via oral gavage. Tail blood samples were collected at 0, 1, 2, 4, and 8 h after dosing to measure the blood glucose using a glucometer (One Touch Ultra, Lifescan, Milpitas, CA).