New potent antihyperglycemic agents in db/db mice: Synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones

Journal of Medicinal Chemistry

Volumn 39, Issue 20, 1996, Pages 3920-3928

  Kees, Kenneth L ^a,b   Fitzgerald Jr , John J ^b   Steiner, Kurt E ^c   Mattes, James F ^b   Mihan, Brenda ^c   Tosi, Theresa ^c   Mondoro, Diane ^c   McCaleb, Michael L ^d  

^a WYETH AYERST RESEARCH   (United States)

^b Cardiovasc Metab Dis Pharmacol   (United States)

^c PFIZER INC   (United States)

^d BAYER CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; HYPERGLYCEMIC AGENT; PHLORIZIN; PYRAZOLONE; UNCLASSIFIED DRUG; WAY 123783;

ALKYLATION; ARTICLE; DRUG SYNTHESIS; GLUCOSE ABSORPTION; GLUCOSE TOLERANCE TEST; GLUCOSURIA; HYPERGLYCEMIA; STRUCTURE ACTIVITY RELATION;

ABSORPTION; ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; GLUCOSE TOLERANCE TEST; GLYCOSURIA; HYPOGLYCEMIC AGENTS; KIDNEY TUBULES; MEMBRANE GLYCOPROTEINS; MICE; MICE, INBRED C57BL; MICE, OBESE; MOLECULAR STRUCTURE; MONOSACCHARIDE TRANSPORT PROTEINS; PYRAZOLES; RATS; RATS, SPRAGUE-DAWLEY; SODIUM-GLUCOSE TRANSPORTER 1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0029793541     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960444z     Document Type: Article

References (26)

1. Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M.; Moore, R. D.; McCaleb, M. L. Studies on New Acidic Azoles as Glucose-Lowering Agents in Obese, Diabetic db/db Mice. J. Med. Chem. 1995, 38, 617-628.
2. 25 values, the effective oral dose for 25% reduction in plasma glucose, have dropped from 40 mg/kg (ciglitazone) to 0.05 mg/ kg for some newer analogs; see: (a) Sohda, T.; Mizuno, K.; Mamose, Y.; Ikeda, H.; Fujita, T.; Meguro, K. Studies on Antidiabetic Agents. 11. Novel Thiazolidinedione Derivatives as Potent Hypoglycemic and Hypolipidemic Agents. J. Med. Chem. 1992, 35, 2617-2626. (b) Another series of potent thiazolidenediones in ob/ob mice have been recently described; see: Hulin, B.; Clark, D. A.; Goldstein, S. W McDermott, R. E.; Dambek, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis, D. M.; Rizzi, J. P. Novel Thiazolidene-2,4-diones as Potent Euglycemic Agents. J. Med. Chem. 1992, 35, 1853-1864.
3. 25 values, the effective oral dose for 25% reduction in plasma glucose, have dropped from 40 mg/kg (ciglitazone) to 0.05 mg/ kg for some newer analogs; see: (a) Sohda, T.; Mizuno, K.; Mamose, Y.; Ikeda, H.; Fujita, T.; Meguro, K. Studies on Antidiabetic Agents. 11. Novel Thiazolidinedione Derivatives as Potent Hypoglycemic and Hypolipidemic Agents. J. Med. Chem. 1992, 35, 2617-2626. (b) Another series of potent thiazolidenediones in ob/ob mice have been recently described; see: Hulin, B.; Clark, D. A.; Goldstein, S. W McDermott, R. E.; Dambek, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis, D. M.; Rizzi, J. P. Novel Thiazolidene-2,4-diones as Potent Euglycemic Agents. J. Med. Chem. 1992, 35, 1853-1864.
4. van der Waals radii for sulfur and half-thickness of a phenyl ring are 1.85 Å; see: Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 3rd ed.; Interscience: New York, 1972; p 120.
5. Hemiketal formation at the trifluoromethyl ketone carbonyl was facile in protic media, and this material was very slow to cyclize with hydrazine.
6. Compound 20 was prepared by starting from commercially available 4-acetyltoluene and protection as the ethylene ketal followed by NBS, steps a and b (Scheme 1), and aqueous HC1.
7. Sodium hydroxide in methanol or ethanol gave similar results.
8. 13C NMR data are given in the Experimental Section.
9. 3) indicates it is not 31.
10. 6) produced an NOE at the N-methyl (δ 3.61), benzylmethylene (δ 3.7), and the two adjacent ortho hydrogens (δ 7.0).
11. + + H).
12. M. L. McCaleb, unpublished results.
13. We have no metabolic data concerning the possible in vivo interconversion of 4 and 5.
14. Four hours after administration of 4 (20 mg/kg), mean plasma glucose levels in db/db mice were decreased 59%; 24 h later, plasma glucose was decreased 22% vs controls.
15. In our hands, neither first-generation (tolbutamide) nor second-generation (glyburide) sulfonylurea agents lowered plasma glucose in fed ob/ob or db/db mice. In db/db mice, glyburide (10 mg/kg/day × 4) did not significantly increase plasma insulin levels.
16. Hulin, B.; McCarthy, P. A.; Gibbs, E. M. The Glitazone Family of Antihyperglycemic Agents. Curr. Pharm. Des. 1996, 2, 85-102.
17. Rossetti, L.; Smith, D.; Schulman, G. I.; Papachristou, D.; DeFronzo, R. A. Correction of Hyperglycemia with Phlorizin Normalizes Tissue Sensitivity to Insulin in Diabetic Rats. J. Clin. Invest. 1987, 79, 1510-1515.
18. All drugs were administered to normal (Swiss CD) mice at 100 mg/kg, po/day × 4 (n = 3). On day 4, mice were placed into Nalgene metabolic cages (each group of three in a single cage) with ad libitum access to food and water. Urine was collected for 20-24 h, and urine glucose levels were qualitatively determined using an Abbot VP autoanalyzer.
19. Urine glucose above 0.1 g/dL was considered "positive" for glucosuria.
20. M. Malamas, I. Gunawan, M. McCaleb, unpublished results. See: Malamas, M. Naphthalenylmethyl Thiophenones as Anti- hyperglycemic Agents. U.S. Patent 5,444,086, 1995.
21. M. Malamas, I. Gunawan, M. McCaleb, unpublished results. See: Malamas, M. Naphthalenylmethyl Thiophenones as Anti- hyperglycemic Agents. U.S. Patent 5,444,086, 1995.
22. Glucosuria: 38, 7.65 g/dL; 42, 7.3 g/dL.
23. +-glucose Cotransporter SGLT2. Delineation of the Major Renal Reabsorptive Mechanism for a D-Glucose. J. Clin. Invest. 1994, 93, 397-404 and references therein.
24. Administration of phlorizin at 200 mg/kg, ip gave similar results.
25. Nor did WAY-123783 block absorption of a subcutaneous infusion of glucose (1 g/kg) given to obese, insulin-resistant Zucker (fa/ fa) rats, after 4 days of drug administration (25 mg/kg/day × 4); on the morning of the fourth day, Zucker rats (n = 4) were fasted for 2 h followed by the fourth administration of WAY-123783. After an additional 1 h fast, glucose (1 g/kg) was administered by subcutaneous infusion. Blood samples were collected from the tail tip at 0 (pre-glucose), 30, 60, 90, and 120 min after glucose. The area under the glucose curve was compared to that of vehicle-treated rats.
26. In one experiment, WAY-123783 administered (100 mg/kg) simultaneously with glucose (2 g/kg, po) to 18 h fasted normal rats significantly inhibited glucose absorption 30 min postdose (∼15% inhibition).