N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent

Journal of Medicinal Chemistry

Volumn 41, Issue 25, 1998, Pages 5055-5069

  Cobb, Jeff E ^a   Blanchard, Steven G ^a   Boswell, Evan G ^a   Brown, Kathleen K ^a   Charifson, Paul S ^a,b   Cooper, Joel P ^a   Collins, Jon L ^a   Dezube, Milana ^a   Henke, Brad R ^a   Hull Ryde, Emily A ^a   Lake, Debra H ^a   Lenhard, James M ^a   Oliver Jr , William ^a   Oplinger, Jeffery ^a   Pentti, Mila ^a   Parks, Derek J ^a   Plunket, Kelli D ^a   Tong, Wei Qin ^a  

^a GLAXOSMITHKLINE   (United States)

^b VERTEX PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [1 CARBOXY 2 [4 [2 (5 METHYL 2 PHENYLOXAZOL 4 YL)ETHOXY]PHENYL]ETHYLAMINO] BENZOIC ACID; 3 [4 [2 (BENZOXAZOL 2 YLMETHYLAMINO)ETHOXY]PHENYL] [(2 BENZOYLPHENYL)AMINO]PROPIONIC ACID; [(2 BENZOYLPHENYL)AMINO] 3 [4 [2 (5 METHYL 2 PHENYLOXAZOL 4 YL)ETHOXY]PHENYL]PROPIONIC ACID; ANTIDIABETIC AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DIABETES MELLITUS; DOSE RESPONSE; DRUG CONFORMATION; DRUG EFFECT; DRUG SYNTHESIS; GLUCOSE METABOLISM; HYPOGLYCEMIA; LIGAND BINDING; LIPOGENESIS; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTILIPEMIC AGENTS; BENZOIC ACIDS; BLOOD GLUCOSE; CELL LINE; DIABETES MELLITUS, EXPERIMENTAL; DNA-BINDING PROTEINS; HUMANS; HYPOGLYCEMIC AGENTS; LIGANDS; LIPIDS; MALE; MICE; OXAZOLES; RADIOLIGAND ASSAY; RATS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION FACTORS; TYROSINE;

EID: 7844232968     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980414r     Document Type: Article

References (24)

1. Reviews on troglitazone: (a) Chen, C. Troglitazone: an antidiabetic agent. Am. J. Health-Syst. Pharm. 1998, 55, 905-925. (b) Horikoshi, H.; Yoshioka, T. Troglitazone - a novel antidiabetic drug for treating insulin resistance. Drug Discovery Today 1998, 3, 79-88. (c) Spencer, C. M.; Markham, A. Troglitazone. Drugs 1997, 54, 89-101.
2. Reviews on troglitazone: (a) Chen, C. Troglitazone: an antidiabetic agent. Am. J. Health-Syst. Pharm. 1998, 55, 905-925. (b) Horikoshi, H.; Yoshioka, T. Troglitazone - a novel antidiabetic drug for treating insulin resistance. Drug Discovery Today 1998, 3, 79-88. (c) Spencer, C. M.; Markham, A. Troglitazone. Drugs 1997, 54, 89-101.
3. Reviews on troglitazone: (a) Chen, C. Troglitazone: an antidiabetic agent. Am. J. Health-Syst. Pharm. 1998, 55, 905-925. (b) Horikoshi, H.; Yoshioka, T. Troglitazone - a novel antidiabetic drug for treating insulin resistance. Drug Discovery Today 1998, 3, 79-88. (c) Spencer, C. M.; Markham, A. Troglitazone. Drugs 1997, 54, 89-101.
4. Clinical trials with troglitazone: (a) Johnson, M. D.; Campbell, L. K.; Campbell, R. K. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann. Pharmacother. 1998, 32, 337-348. (b) Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823. (c) Inzucchi, S. E.; Maggs, D. G.; Spollett, G. R.; Page, S. L.; Rife, F. S.; Walton, V.; Shulman, G. I. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 1998, 338, 867-872. (d) Maggs, D. G.; Buchanan, T. A.; Burant, C. F.; Cline, G.; Gumbiner, B.; Hsueh, W. A.; Inzucchi, S.; Kelley, D.; Nolan, J.; Olefsky, J. M.; Polonsky, K. S.; Silver, D.; Valiquett, T. R.; Shulman, G. I. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann, Intern. Med. 1998, 128, 176-185. (e) Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
5. Clinical trials with troglitazone: (a) Johnson, M. D.; Campbell, L. K.; Campbell, R. K. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann. Pharmacother. 1998, 32, 337-348. (b) Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823. (c) Inzucchi, S. E.; Maggs, D. G.; Spollett, G. R.; Page, S. L.; Rife, F. S.; Walton, V.; Shulman, G. I. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 1998, 338, 867-872. (d) Maggs, D. G.; Buchanan, T. A.; Burant, C. F.; Cline, G.; Gumbiner, B.; Hsueh, W. A.; Inzucchi, S.; Kelley, D.; Nolan, J.; Olefsky, J. M.; Polonsky, K. S.; Silver, D.; Valiquett, T. R.; Shulman, G. I. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann, Intern. Med. 1998, 128, 176-185. (e) Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
6. Clinical trials with troglitazone: (a) Johnson, M. D.; Campbell, L. K.; Campbell, R. K. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann. Pharmacother. 1998, 32, 337-348. (b) Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823. (c) Inzucchi, S. E.; Maggs, D. G.; Spollett, G. R.; Page, S. L.; Rife, F. S.; Walton, V.; Shulman, G. I. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 1998, 338, 867-872. (d) Maggs, D. G.; Buchanan, T. A.; Burant, C. F.; Cline, G.; Gumbiner, B.; Hsueh, W. A.; Inzucchi, S.; Kelley, D.; Nolan, J.; Olefsky, J. M.; Polonsky, K. S.; Silver, D.; Valiquett, T. R.; Shulman, G. I. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann, Intern. Med. 1998, 128, 176-185. (e) Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
7. Clinical trials with troglitazone: (a) Johnson, M. D.; Campbell, L. K.; Campbell, R. K. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann. Pharmacother. 1998, 32, 337-348. (b) Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823. (c) Inzucchi, S. E.; Maggs, D. G.; Spollett, G. R.; Page, S. L.; Rife, F. S.; Walton, V.; Shulman, G. I. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 1998, 338, 867-872. (d) Maggs, D. G.; Buchanan, T. A.; Burant, C. F.; Cline, G.; Gumbiner, B.; Hsueh, W. A.; Inzucchi, S.; Kelley, D.; Nolan, J.; Olefsky, J. M.; Polonsky, K. S.; Silver, D.; Valiquett, T. R.; Shulman, G. I. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann, Intern. Med. 1998, 128, 176-185. (e) Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
8. Clinical trials with troglitazone: (a) Johnson, M. D.; Campbell, L. K.; Campbell, R. K. Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus. Ann. Pharmacother. 1998, 32, 337-348. (b) Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823. (c) Inzucchi, S. E.; Maggs, D. G.; Spollett, G. R.; Page, S. L.; Rife, F. S.; Walton, V.; Shulman, G. I. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 1998, 338, 867-872. (d) Maggs, D. G.; Buchanan, T. A.; Burant, C. F.; Cline, G.; Gumbiner, B.; Hsueh, W. A.; Inzucchi, S.; Kelley, D.; Nolan, J.; Olefsky, J. M.; Polonsky, K. S.; Silver, D.; Valiquett, T. R.; Shulman, G. I. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann, Intern. Med. 1998, 128, 176-185. (e) Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
9. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W., Jr.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J.; Mook, R. A.; Noble, S. A.; Oliver, W., Jr.; Parks, D. J.; Plunker, K. D.; Szewczyk, J. W.; Willson, T. M. N-(2-Benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem. 1998, 41, 5020-5036.
10. Hulin, B.; Newton, L. S.; Lewis, D. M.; Genereux, P. E.; Gibbs, E. M.; Clark, D. E. Hypoglycemic activity of a series of α-alkylthio and α-alkoxy carboxylic acids. J. Med. Chem. 1996, 39, 3897.
11. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith, D. G.; Smith, S. A. Non thiazolidinedione antihyperglycemic agents. 1: α-heteroatom substituted β-phenylpropanoic acids. Bioorg. Med. Chem. Lett. 1996, 6, 2121.
12. M. Milburn, unpublished results from these laboratories. A detailed description of the X-ray crystal structure of ligand-bound hPPARγ will be the subject of a future report.
13. Adams, J.; Spero, D. M. Rhodium(II) catalyzed reactions of diazocarbonyl compounds. Tetrahedron 1991, 47, 1765-1808.
14. Haigh, D.; Sime, J. T. Heterocyclic compounds as pharmaceuticals. PCT Int. Appl. WO 9401420 Al.
15. Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A. Synthesis of un symmetrical biaryl ketones via palladium-catalyzed carbonylative cross-coupling reaction of arylboronic acids with iodoarenes. Tetrahedron Lett. 1993, 34, 7595-7598.
16. Frye, S. V.; Johnson, M. C.; Valvano, N. L. Synthesis of 2-aminobenzophenones via rapid halogen-lithium exchange in the presence of a 2-amino-N-methoxy-N-methylbenzamide. J. Org. Chem. 1991, 56, 3750-3752.
17. Cantello, B. C. C.; Cawthorne, M. A.; Cottam, G. P.; Duff, P. T.; Haigh, D.; Hindley, R. M.; Lister, C. A.; Smith, S. A.; Thurlby, P. L. [[ω-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J. Med. Chem. 1994, 37, 3977-3985.
18. 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 thiazolidine-2,4-diones as potent euglycemic agents. J. Med. Chem. 1992, 35, 1853-1864.
19. Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S. Simple and convenient method for the preparation of α-substituted α-diazoesters. Tetrahedron Lett. 1971, 4495-4498.
20. Clark, J. B.; Palmer, C. J.; Shaw, W. N. The diabetic zucker fatty rat. Proc. Soc. Exp. Biol. Med. 1983, 173, 68-75.
21. Nathan, D. M.; Singer, D. E.; Hurxthal, K.; Goodson, J. D. The clinical information value of the glycosylated hemoglobin assay. N. Engl. J. Med. 1984, 310, 341-346.
22. Howard, A. S.; Meerholz, C. A.; Michael, J. P. Synthesis of 1,3-diketones from lithium enolates and acyl cyanides. Tetrahedron Lett. 1979, 1339-1340.
23. Walsh, D. A.; Moran, H. W.; Shamblee, D. A.; Welstead, W. J., Jr.; Nolan, J. C.; Sancilio, L. F.; Graff, G. Antiinflammatory agents. 4. Syntheses and biological evaluation of potential prodrugs of 2-amino-3-benzoylbenzeneacetic acid and 2-amino-3-(4-chlorobenzoyl)benzeneacetic acid. J. Med. Chem. 1990, 33, 2296-2304.
24. Hromatka, O.; Binder, D.; Eichinger, K. Synthesis and proof of structure of substituted 5-phenyl-1H-thieno[3,4-e]-1,4-diazepin-2(3H)-ones. Monatsh. Chem. 1973, 104, 1599-1606.