Discovery and structure-activity relationships of trisubstituted pyrimidines/pyridines as novel calcium-sensing receptor antagonists

Journal of Medicinal Chemistry

Volumn 52, Issue 4, 2009, Pages 1204-1208

  Yang, Wu ^a   Ruan, Zheming ^a   Wang, Yufeng ^a   Van Kirk, Katy ^a   Zhengping, Ma ^a   Arey, Brian J ^a   Cooper, Christopher B ^a   Seethala, Ramakrishna ^a   Feyen, Jean H M ^a   Dickson Jr , John K ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 4 (3,4,5 TRIMETHOXYPHENYL)PYRIMIDINE 5 CARBOXAMIDE; CALCIUM SENSING RECEPTOR; CALCIUM SENSING RECEPTOR ANTAGONIST; PARATHYROID HORMONE; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG EFFICACY; DRUG POTENCY; DRUG SOLUBILITY; HORMONE RELEASE; IN VIVO STUDY; OSTEOPOROSIS; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; DRUG DISCOVERY; HUMANS; INHIBITORY CONCENTRATION 50; OSTEOPOROSIS; PARATHYROID HORMONE; PYRIDINES; PYRIMIDINES; RECEPTORS, CALCIUM-SENSING; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 64349117373     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm801178c     Document Type: Article

References (20)

1. (a) Brown, E. M.; Gamba, G.; Riccardi, D.; Lombardi, M.; Butters, R.; Kifor, O.; Sun, A.; Hediger, M. A.; Lytton, J.; Hebert, S. C. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993, 366, 575-80.
2. (b) Brown, E. M.; Pollak, M.; Riccardi, D.; Hebert, S. C. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from parathyroid and kidney: new insights into the physiology and pathophysiology of calcium metabolism. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association. Eur. Renal Assoc. 1994, 9, 1703-6.
3. Brown, E. M.; MacLeod, R. J. Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 2001, 81, 239-297.
4. 2+-sensing receptor. J. Biol. Chem. 1996, 271, 19537-19545.
5. (a) Dempster, D. W.; Cosman, F.; Parisien, M.; Shen, V.; Lindsay, R. Anabolic actions of parathyroid hormone on bone. Endocr. Rev. 1993, 14, 690-709.
6. (b) Kimmel, D. B.; Bozzato, R. P.; Kronis, K. A.; Coble, T.; Sindrey, D.; Kwong, P.; Recker, R. R. The effect of recombinant human (1 -84) or synthetic human (1 -34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats. Endocrinology 1993, 132, 1577-1584.
7. (a) Nemeth, E. F. Pharmacological regulation of parathyroid hormone secretion. Curr. Pharm. Des. 2002, 8, 2077-2087.
8. (b) Nemeth, E. F.; Delmar, E. G.; Heaton, W. L.; Miller, M. A.; Lambert, L. D.; Conklin, R. L.; Gowen, M.; Gleason, J. G.; Bhatnagar, P. K.; Fox, J. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther. 2001, 299, 323-331.
9. Gowen, M.; Stroup, G. B.; Dodds, R. A.; James, I. E.; Votta, B. J.; Smith, B. R.; Bhatnagar, P. K.; Lago, A. M.; Callahan, J. F.; DelMar, E. G.; Miller, M. A.; Nemeth, E. F.; Fox, J. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest. 2000, 105, 1595-1604.
10. (a) Yang, W.; Wang, Y.; Roberge, J. Y.; Ma, Z.; Liu, Y.; Lawrence, R. M.; Rotella, D. P.; Seethala, R.; Feyen, J. H. M.; Dickson, J. K., Jr. Discovery and structure-activity relationships of 2-benzylpyrro-lidine-substituted aryloxypropanols as calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 1225-1228.
11. (b) Shcherbakova, I.; Balandrin, M. F.; Fox, J.; Ghatak, A.; Heaton, W. L.; Conklin, R. L. 3H-Quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis. Bioorg. Med. Chem. Lett. 2005, 15, 1557-1560.
12. (c) Shcherbakova, I.; Huang, G.; Geoffroy, O. J.; Nair, S. K.; Swierczek, K.; Balandrin, M. F.; Fox, J.; Heaton, W. L.; Conklin, R. L. Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones. Bioorg. Med. Chem. Lett. 2005, 15, 2537-2540.
13. (d) Gavai, A. V.; Vaz, R. J.; Mikkilineni, A. B.; Roberge, J. Y.; Liu, Y.; Lawrence, R. M.; Corte, J. R.; Yang, Wu; Bednarz, M.; Dickson, J. K.; Ma, Z.; Seethala, R.; Feyen, J. H. M. Discovery of novel 1-arylm-ethylpyrrolidin-2- ylethanolamines as calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 5478-5482.
14. (e) Kessler, A.; Faure, H.; Petrel, C.; Rognan, D.; Cesario, M.; Ruat, M.; Dauban, P.; Dodd, R. H. N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-di- aminocyclohexanes: development of 4-chlorophenylcarboxamide (Cal-hex 231) as a new calcium sensing receptor ligand demonstrating potent calcilytic activity. J. Med. Chem. 2006, 49, 5119-5128.
15. Arey, B. J.; Seethala, R.; Ma, Z.; Fura, F.; Morin, J.; Swartz, J.; Vyas, V.; Yang, W.; Dickson, J. K., Jr.; Feyen, J. H. M. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion. In Vivo Endocrinol. 2005, 146, 2015.
16. Yang, W.; Wang, Y.; Corte, J. R. An efficient synthesis of 2-aryl-6-chloronicotinamides via PXPd2 catalyzed regioselective Suzuki coupling. Org. Lett. 2003, 5, 3131-3134.
17. Hu, J.; Jiang, J.; Costanzi, S.; Thomas, C.; Yang, W.; Feyen, J. H. M.; Jacobson, K. A.; Spiegel, A. M. A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator. J. Biol. Chem. 2006, 281, 21558-21565.
18. Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. A safe, economical method for the preparation of β-oxo esters. Synthesis 1993, 3, 290-292.
19. Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. Chemistry of oxaziridines. 9. Synthesis of 2-sulfonyl-and 2-sulfamy- loxaziridines using potassium peroxymonosulfate (Oxone). J. Org. Chem. 1988, 53, 2087-2089.
20. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. 1H-Pyrazole-1-carboxamidine hydrochloride an attractive reagent for guanylation of amines and its application to peptide synthesis. J. Org. Chem. 1992, 57, 2497-2502.