5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity

Journal of Medicinal Chemistry

Volumn 41, Issue 10, 1998, Pages 1568-1573

  Gagliardi, Stefania ^a   Nadler, Guy ^b   Consolandi, Emanuela ^a   Parini, Carlo ^a   Morvan, Marcel ^b   Legave, Marie Nöelle ^a   Belfiore, Pietro ^a   Zocchetti, Andrea ^a   Clarke, Geoffrey D ^a   James, Ian ^c   Nambi, Ponnal ^c   Gowen, Maxine ^c   Farina, Carlo ^a  

^a SmithKline Beecham SpA   (Italy)

^b SmithKline Beecham Research Unit   (France)

^c GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5 (5,6 DICHLORO 2 INDOLYL) 2 METHOXY N [3 [4 (2 PYRIMIDINYL)PIERAZIN 1 YL]PROPYL 2,4 PENTADIENAMIDE; 5 (5,6 DICHLORO 2 INDOLYL) 2 METHOXY N [4(2,2,6,6 TETRAMETHYL)PIPERIDINYL] 2,4 PENTADIENAMIDE; 5 (5,6 DICHLORO 2 INDOLYL) 2 METHOXY N [8 METHYL 8 AZABICYCLO[3.2.2]OCT 3 YL] 2,4 PENTADIENAMIDE; 5 (5,6 DICHLORO 2 INDOLYL) N [3 (DIETHYLAMINO)PROPYL] 2 METHOXY 2,4 PENTADIENAMIDE; ADENOSINE TRIPHOSPHATASE INHIBITOR; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CHICKEN; DRUG ACTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; NONHUMAN; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS;

ANIMALS; BICYCLO COMPOUNDS, HETEROCYCLIC; BONE RESORPTION; CELL MEMBRANE; CHICKENS; ENZYME INHIBITORS; HUMANS; INDOLES; KIDNEY CORTEX; OSTEOCLASTS; PROTON-TRANSLOCATING ATPASES; PYRIMIDINES; TUMOR CELLS, CULTURED; VACUOLES;

EID: 14444282582     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9800144     Document Type: Article

References (31)

1. Baron, R.; Neff, L.; Louvard, D.; Courtoy, P. J. Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100 kD lysosomal membrane protein at the osteoclast ruffled border. J. Cell Biol. 1985, 101, 2210-2222.
2. Hall, T. J.; Chambers, T. J. Molecular aspects of osteoclast function. Inflamm. Res. 1996, 45, 1-9.
3. Blair, H. C.; Teitelbaum, S. M.; Ghiselli, R.; Gluck, S. Osteo-clastic bone resorption by a polarized vacuolar proton pump. Science 1989, 245, 855-857.
4. Schlesinger, P. H.; Blair, H. C.; Teitelbaum, S. L.; Edwards, J. C. Characterization of the osteoclast ruffled border chloride channel and its role in bone resorption. J. Biol. Chem. 1997, 272, 18636-18643.
5. Bowman, E. M.; Siebers, A.; Altendorf, K. Bafilomycins: a Class of Inhibitors of Membrane ATPases from Microorganisms, Animal Cells, and Plant Cells. Proc. Natl Acad. Sci. U.S.A. 1988, 85, 7972-7976.
6. +translocating ATPases. Biochim. Biophys. Acta 1991, 1065 (2), 261-268.
7. 1 abolishes bone resorption. Biochem. Biophys. Res. Commun. 1990, 168, 309-313.
8. 1 inhibits bone resorption in vivo after systemic administration. J. Bone Miner. Res. 1995, 10 (Suppl. 1), S296.
9. +-ATPase: a universal proton pump of eukaryotes. Biochem. J. 1997, 324, 697-712.
10. +ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J. Biol. Chem. 1991, 266, 17707-17712.
11. +-ATPase with bafilomycin reduces delivery of internalized molecules from mature multivesicular endosomes in HEp-2 cells. Eur. J. Cell Biol. 1996, 69, 343-350.
12. +-ATPase and induces lysosomal enzyme secretion in macrophages. J. Cell Physiol. 1995, 163, 137-144.
13. Stone, D. K.; Xie, X. S. Proton translocating ATPases: issues in structure and function. Kidney Int. 1988, 33, 767-774.
14. +-ATPases. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 6257-6261.
15. +-ATPase. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6087-6091.
16. Li, Y.-P.; Chen, W.; Stashenko, P. Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit. Biochem. Biophys. Res. Commun. 1996, 218, 813-821.
17. +ATPases. Biochemistry 1993, 32, 2808-2812.
18. Mattsson, J. P.; Wallmark, B.; Lorentzon, P.; Keeling, D. J. Characterization of proton transport in bone-derived membrane vesicles. Acta Physiol. Scand. 1992, 146, 253-257.
19. +-ATPase. Bone Miner. 1994, 27, 159-166.
20. +-ATPase is highly expressed in human osteoclasts. Biochem. Biophys. Res. Commun. 1995, 214, 1108-1113.
21. +ATPase. J. Med. Chem., accepted for publication.
22. +- ATPase type in the ruffled borders of osteoclasts. J. Cell Biol. 1990, 111, 1305-1311.
23. Cidon, S.; Nelson, N. A novel ATPase in the chromaffin granule membrane. J. Biol. Chem. 1983, 258, 2892-2898.
24. +-ATPase. J. Biol. Chem. 1990, 265, 21957-21965.
25. Ruggli, P.; Zaeslin, H. Two new dichloro-o-nitrobenzoic acids. Helv. Chim. Acta 1936, 19, 434-439.
26. Engelhardt, M.; Plieninger, H.; Schreiber, P. Zur dartstellung von brenztraubensaüre-enoläthern durch Wittig-Reaktion. (Preparation of pyruvic acid enol ethers by the Wittig reaction.) Chem. Ber. 1964, 97, 1713-1715.
27. Votta, B. J.; Levy, M. A.; Badger, A.; Bradbeer, J.; Dodds, R. A.; James, I. E.; Thompson, S.; Bossard, M. J.; Carr, T.; Connor, J. R.; Tomaszek, T. A.; Szewczuk, L.; Drake, F. H.; Veber, D. F.; Gowen, M. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J. Bone Miner. Res. 1997, 12, 1396-1405.
28. Foged, N. T.; Delaisse, J.-M.; Hou, P.; Lou, H.; Sato, T.; Winding, B.; Bonde, M. Quantification of the collagenolytic activity of isolated osteoclasts by enzyme-linked immunosorbent assay. J. Bone Miner. Res. 1996, 11, 226-237.
29. 2+-stimulated ATPase activity. Anal. Biochem. 1986, 157, 375-380.
30. Burstone, M. S. Histochemical demostration of acid phosphatases with naphthol AS-phosphatases. J. Natl. Cancer Inst. 1958, 21, 523-540.
31. Doster, P.; Imbert, T.; Langlois, M.; Bucher, B.; Mocquet, G. Studies on the neuroleptic benzamides. III- Synthesis and antidopaminergic properties of new 3-nortropane derivatives. Eur. J. Med. Chem. 1984, 19, 105-110.