Nonpeptide αvβ3 antagonists. Part 11: Discovery and preclinical evaluation of potent αvβ 3 antagonists for the prevention and treatment of osteoporosis

Journal of Medicinal Chemistry

Volumn 47, Issue 20, 2004, Pages 4829-4837

  Coleman, Paul J ^a   Brashear, Karen M ^a   Askew, Ben C ^a   Hutchinson, John H ^a   McVean, Carol A ^a   Duong, Le T ^a   Feuston, Bradley P ^a   Fernandez Metzler, Carmen ^a   Gentile, Michael A ^a   Hartman, George D ^a   Kimmel, Donald B ^a   Leu, Chih Tai ^a   Lipfert, Lorraine ^a   Merkle, Kara ^a   Pennypacker, Brenda ^a   Prueksaritanont, Thomayant ^a   Rodan, Gideon A ^a   Wesolowski, Gregg A ^a   Rodan, Sevgi B ^a   Duggan, Mark E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (METHYLPYRIMIDIN 5 YL) 9 (5,6,7,8 TETRAHYDRO[1,8]NAPHTHYRIDIN 2 YL)NONANOIC ACID; 3 PYRIMIDIN 5 YL 9 (5,6,7,8 TETRAHYDRO[1,8]NAPHTHYRIDIN 2 YL)NONANOIC ACID; NONANOIC ACID; RECEPTOR; UNCLASSIFIED DRUG; 3 (METHYLPYRIMIDIN 5 YL) 9 (5,6,7,8 TETRAHYDRO (1,8)NAPHTHYRIDIN 2 YL)NONANOIC ACID; 3 PYRIMIDIN 5 YL 9 (5,6,7,8 TETRAHYDRO (1,8)NAPHTHYRIDIN 2 YL)NONANOIC ACID; 3-(METHYLPYRIMIDIN-5-YL)-9-(5,6,7,8-TETRAHYDRO-(1,8)NAPHTHYRIDIN-2-YL)NONANOIC ACID; 3-PYRIMIDIN-5-YL-9-(5,6,7,8-TETRAHYDRO-(1,8)NAPHTHYRIDIN-2-YL)NONANOIC ACID; ALPHAVBETA5 INTEGRIN; INTEGRIN; NAPHTHYRIDINE DERIVATIVE; VITRONECTIN RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE TURNOVER; CONTROLLED STUDY; DOG; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SCREENING; FEMALE; IC 50; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; OSTEOPOROSIS; PLASMA; RAT; RHESUS MONKEY; ANIMAL; BIOAVAILABILITY; BONE DENSITY; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG ANTAGONISM; DRUG EFFECT; HUMAN; MACACA; METABOLISM; METHODOLOGY; ORAL DRUG ADMINISTRATION; OSTEOLYSIS; OVARIECTOMY; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; BONE DENSITY; BONE RESORPTION; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; FEMALE; HUMANS; INHIBITORY CONCENTRATION 50; INTEGRINS; MACACA MULATTA; MODELS, MOLECULAR; NAPHTHYRIDINES; OSTEOPOROSIS; OVARIECTOMY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, VITRONECTIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 4544384606     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049874c     Document Type: Article

References (39)

1. Graul, A. I.; Sorbera, L. A.; Prous, J. R. Osteoporosis. Drugs Today 2001, 37, 703-722.
2. (a) Ershler, W. B. New Concepts in the Pathogenesis and Treatment of Osteoporosis. Front. Biomed. 2000, 1, 41-51.
3. (b) Eastell, R. Treatment of Postmenopausal Osteoporosis. N. Engl. J. Med. 1998, 338, 736.
4. Duong, L. T.; Rodan, G. A. Integrin-Mediated Signaling in the Regulation of Osteoclast Adhesion and Activation. Front. Biosci. 1998, 3, d757-d768.
5. 3. Expert. Opin. Ther. Pat. 2002, 12, 1009-1021.
6. 3 (the Vitronectin Receptor) Drug Discovery Today 2000, 5, 397-408.
7. 3 Integrin Antagonists as Inhibitors of Bone Resorption. Expert. Opin. Invest. Drugs 2000, 9, 1281-1291.
8. Fisher, J. E.; Caulfield, M. P.; Sato, M.; Quartuccio, H. A.; Gould, R. J.; Garsky, V. M.; Rodan, G. A.; Rosenblatt, M. Inhibition of Osteoclastic Bone Resorption in Vivo by Echistatin, an "Arginyl-Glycyl-Aspartyl" (RGD)-Containing Protein. Endocrinology 1993, 132, 1411-1413.
9. Yamamoto, M.; Fisher, J. E.; Gentile, M.; Seedor, J. G.; Leu, C.-T.; Rodan, S. B.; Rodan, G. A. The Integrin Ligand Echistatin Prevents Bone Loss in Ovariectomized Mice and Rats. Endocrinology 1998, 139, 1411.
10. 3 Integrin Inhibits Osteoclast-Mediated Bone Resorption in the Thyroparathyroidectomized Rat. Endocrinology 1996, 137, 918.
11. 3 Integrin Inhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo. J. Clin. Invest. 1997, 99, 2284-2292.
12. Lark, M. W.; Stroup, G. B.; Hwang, S. M.; James, I. E.; Rieman, D. J.; Drake, F. H.; Bradbeer, J. N.; Mathur, A.; Erhard, K. F.; Newlander, K. A.; Ross, S. T.; Salyers, K. L.; Smith, B. R.; Miller, W. H.; Huffman, W. F.; Gowen, M. Design and Characterization of Orally Active Arg-Gly-Asp Peptidomimetic Vitronectin Receptor Antagonist SB 265123 for Prevention of Bone Loss in Osteoporosis. J. Pharmacol. Exp. Ther. 1999, 291, 612-617.
13. Miller, W. H.; Alberts, D. P.; Bhatnagar, P. K.; Bondinell, W. E.; Callahan, J. F.; Calvo, R. R.; Cousins, R. D.; Erhard, K. F.; Heerding, D. A.; Keenan, R. M.; Kwon, C.; Manley, P. J.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas, I. N.; Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.; Hwang, S.-W.; James, I. E.;, Lark, M. W.; Rieman, D. J.; Stroup, G. B.; Azzarano, L. M.; Salyers, K. L.; Smith, B. R.; Ward, K. W.; Johanson, K. O.; Huffman, W. F. Discovery of Orally Active Nonpeptide Vitronectin Receptor Antagonists Based on a 2-Benzazepine Gly-Asp Mimetic. J. Med. Chem. 2000, 43, 22-26.
14. Hoffman, S. J.; Vasko-Moser, J.; Miller, W. H.; Lark, M. W.; Gowen, M.; Stroup, G. Rapid Inhibition of Thyroxine-Induced Bone Resorption in the Rat by an Orally Active Vitronectin Receptor Antagonist. J. Pharm. Exp. Ther. 2002, 302, 205.
15. 3 Antagonist for the Prevention and Treatment of Osteoporosis. J. Med. Chem. 2003, 46, 4790-4798.
16. 3 Antagonists. Part 4: Potent and Orally Bioavailable Chain-Shortened RGD Mimetics. Bioorg. Med. Chem. Lett. 2002, 12, 2463-2465.
17. 3 Antagonists. Part 3: Identification of Potent RGD Mimetics Incorporating Novel β-Amino Acids as Aspartic Acid Replacements. Bioorg. Med. Chem. Lett. 2002, 12, 31-34.
18. 3 Antagonists. Identification of Potent, Chain-Shortened RGD Mimetics that Incorporate a Central Pyrrolidinone Constraint. Bioorg. Med. Chem. Lett., accepted for publication, 2003.
19. Wang, J.; Breslin, M. J.; Coleman, P. J.; Duggan, M. E.; Hunt, C. A.; Hutchinson, J. H.; Leu, C.-T.; Rodan, S. B.; Rodan, G. A.; Hartman, G. D. Nonpeptide Antagonists: 3-Substituted Tetrahydro-[1,8]naphthyridine Derivatives. Bioorg. Med. Chem. Lett. 2004, 14, 1049-1052.
20. 3 Antagonists. Part 5: Identification of Potent RGD Mimetics Incorporating 2-Aryl β-Amino Acids as Aspartic Acid Replacements. Bioorg. Med. Chem. Lett. 2002, 12, 3483-3486.
21. 3 Antagonists. Part 10: In Vitro and in Vivo Evaluation of a Potent 7-Methyl Substituted Tetrahydro-[1,8]naphthyridine. Bioorg. Med. Chem. Lett. 2004, 14, 4515-4518.
22. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. Simple Stereoselective Version of the Claisen Rearrangement Leading to Trans-Trisubstituted Olefinic Bonds. Synthesis of Squalene. J. Am. Chem. Soc. 1970, 92, 741-743.
23. Rivera, N. R.; Hsiao, Y.; McWilliams, C.; Cowen, J. A.; Armstrong, J.; Yasuda, N.; Hughes, D. L. Highly Efficient Synthesis of 2-Amino-3- Pyridinecarboxaldehyde. Synth. Commun. 2001, 31, 1573-1579.
24. Dormer, P. G.; Eng, K. K.; Fair, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P. Highly Regioselective Friedlaender Annulations with Unmodified Ketones Employing Novel Amine Catalysts: Syntheses of 2-Substituted Quinolines, 1,8-Naphthyridines, and Related Heterocycles. J. Org. Chem. 2003, 68, 467-477.
25. 2) to regenerate 11 and recycled.
26. 2(g, 1 atm) tended to reduce the pyrimidine 3-substituent.
27. Coleman, P. J.; Hutchinson, J. H.; Hunt, C. A.; Lu, P.; Delaporte, E.; Rushmore, T. Syntheses of 5- and 6-[2,3]-Dihydrobenzofuran β-Amino Acids. Tetrahedron Lett. 2000, 41, 5803-5806.
28. Kotsuki, H., Datta, P. K., Suenaga, H. An Efficient Procedure for Palladium-Catalyzed Hydroformylation of Aryl/Enol Tri-flates. Synthesis 1996, 470-472.
29. Rho, T.; Abuh, Y. F. One-Pot Synthesis of Pyrimidine-5-carboxaldehyde and Ethyl Pyrimidine-5-carboxylate by Utilizing Pyrimidin-5-yl-lithium. Synth. Commun. 1994, 24, 253-256.
30. (a) Gupton, J. T.; Gall, J. E.; Riesinger, S. W.; Smith, S. Q.; Bevirt, K. M.; Sikorski, J. A.; Dahl, M. L.; Arnold, Z. An Alternative Preparation of the 2-Dimethylaminomethylene-1,3-bis(dimethylimmonio)propane Salt from Phosphonoacetic Acids and Some Applications in Heterocyclic Synthesis. J. Heterocycl. Chem. 1991, 28, 1281-5.
31. (b) Keshavarz-K., M.; Cox, S. D.; Angus, R. O., Jr.; Wudl, F. An improved isolation of triformyl-methane (TFM): Properties and Preparation of Some Derivatives. Synthesis 1988, 8, 641-644.
32. 3 Antagonist. J. Med. Chem. 2000, 43, 3736-3745.
33. Cox, M. T.; Heaton, D. W.; Horbury, J. Preparation of Protected trans Olefinic Dipeptide Isosteres. J. Chem. Soc., Chem. Commun. 1980, 17, 799-800.
34. log P. Measured from octanol, pH 7.4 buffer.
35. Protein binding. Human plasma binding measured in a high-throughput manner using ultrafiltration of diluted plasma in a pH 7.4 buffer. The analysis is conducted at room temperature, and solutions are analyzed by HPLC.
36. Kimmel, D. Animal Models for In Vivo Experimentation in Osteoporosis Research. In Osteoporosis; Marcus, R., Feldman, D., Kelsey, J., Eds.; Academic Press: San Diego, CA, 1996; pp 671-690.
37. 3 receptor was measured by inhibition of ADP-stimulated aggregation of human gel-filtered platelets. See Hutchinson, J. H.; Cook, J. J.; Brashear, K. M.; Breslin, M. J.; Glass, J. D.; Gould, R. J.; Halczenko, W.; Holahan, M. A.; Lynch, R. J.; Sitko, G. R.; Stranieri, M. T.; Hartman, G. D. Nonpeptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,4-Dihydro-1(1H)- isoquinolinone-Based Antagonists and Ethyl Ester Prodrugs. J. Med. Chem. 1996, 39, 4583-4591.
38. 3 Integrin. J. Med. Chem. 2002, 45, 5640-5648.
39. Sirisoma, N. S.; Johnson, C. R. α-Iodocycloalkenones: Synthesis of (±)-Epibatidine. Tetrahedron Lett. 1998, 39, 2059.