Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine scaffold

Journal of Combinatorial Chemistry

Volumn 3, Issue 6, 2001, Pages 546-553

  Nilsson, Jonas W ^a   Thorstensson, Fredrik ^a   Kvarnström, Ingemar ^a   Oprea, Tudor ^b   Samuelsson, Bertil ^b,c,d   Nilsson, Ingemar ^b  

^a LINKÖPING UNIVERSITY   (Sweden)

^b ASTRAZENECA R AND D   (Sweden)

^c MEDIVIR AB   (Sweden)

^d STOCKHOLM UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

4 PHENYL 2 CARBOXY PIPERAZINE; 4-PHENYL-2-CARBOXY-PIPERAZINE; CALCIUM CHANNEL BLOCKING AGENT; DIHYDROPYRIDINE DERIVATIVE; PIPERAZINE DERIVATIVE;

ARTICLE; CHEMISTRY; COMBINATORIAL CHEMISTRY; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

CALCIUM CHANNEL BLOCKERS; CHEMISTRY, PHARMACEUTICAL; COMBINATORIAL CHEMISTRY TECHNIQUES; DIHYDROPYRIDINES; PIPERAZINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0035515753     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc010013o     Document Type: Article

References (43)

1. Sternbach, L. H. J. Med. Chem. 1979, 22, 1-7.
2. Bock, M. G.; Dipardo, R. M.; Evans, B. E.; Rittle, K. E.; Whitter, W. L.; Veber, D. F.; Andersson, P. S.; Freidinger, R. M. J. Med. Chem. 1989, 32, 13-16.
3. Romer, D.; Buscher, H. M.; Hill, R. C.; Maurer, R.; Petcher, T. J.; Zeugner, H.; Benson, W.; Finner, E.; Milkowski, W.; Thies, P. W. Nature (London) 1982, 298, 759-760.
4. (a) Kornecki, E.; Ehrlich, Y. H.; Lennox, R. H. Science 1984, 226, 1454.
5. (b) Hsu, M. C.; Schutt, A. D.; Holly, M.; Slice, L. W.; Sherman, M. I.; Richman, D. D.; Potash, M. J.; Volsky, D. J. Science 1991, 254, 1799-1802.
6. (c) Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M. J.; Breslin, H. J.; Raeymaeckers, A.; Van Gelder, J.; Woestenborghs, R.; Heykants, J.; Schellekens, K.; Janssen, M. A. C.; Clerq, E. D.; Janssen, P. A. J. Nature (London) 1990, 343, 470-474.
7. (d) James, G. L.; Goldstein, J. L.; Brown, M. S.; Rawson, T. E.; Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson, A. D.; Marsters, J. C., Jr. Science 1993, 260, 1937-1942.
8. Bunin, B. A.; Plunkett, M. J.; Ellman, J. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4708-4712.
9. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnsson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S. E.; Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34, 2525.
10. Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W.; McDevitt, R.; Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med. Chem. 2000, 43, 1293-1310.
11. Murugesan, N.; Gu, Z.; Stein, P. D.; Spergel, S.; Mathu, A.; Leith, L.; Liu, E. C. K.; Zhang, R., Bird, E.; Waldron, T.; Marino, A.; Morrison, R. A.; Webb, M. L.; Moreland, S.; Barrish, J. C. J. Med. Chem. 2000, 43, 3111-3117.
12. Pinto, D. J.; Batt, D. G.; Pitts, W. J.; Petraitis, J. J.; Orwat, M. J.; Wang, S.; Jetter, J. W.; Sherk, S. R.; Houghton, G. C.; Copeland, R. A.; Covington, M. B.; Trzaskos, J. M.; Magolda, R. L. Bioorg. Med. Chem. Lett. 1999, 9, 919-24.
13. (a) Dolle, R. E. Mol. Diversity 1998, 3, 199-233.
14. (b) Dolle, R. E. J. Comb. Chem. 2000, 2, 383-433.
15. (c) Dolle, R. E.; Nelson, K. H., Jr. J. Comb. Chem. 1999, 1, 235-282 and references therein.
16. Available from MDL Information Systems, http:// www.mdli.com/dats/pharmdb.html. The MDDR database is a compilation of over 100 000 pharmaceutically interesting compounds, developed in cooperation with Prous Science Publishers, http://www.prous.com/index.html.
17. Morita, S.; Ootsubo, K.; Uchida, M. JP 05078326, 1993.
18. Bell, I. M.; Freidinger, R. M.; Guare, J. P.; Sparks, M. A.; Williams, P. D. GB 02326639; US 5968938, 1999.
19. Bigge, C. F.; Hays, S. J.; Novak, P. M.; Drummond, J. T.; Johnson, G.; Bobovski, T. P. Tetrahedron Lett. 1989, 30, 5193-5196.
20. Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 30, 6359-6362.
21. The Wang-linker was activated as the p-nitrophenyl carbonate by treating the PS-Wang resin with p-nitrophenyl chloroformate and NMM in DCM.
22. Theoretical loading was determined by cleavage of a weight sample of resin followed by analysis on HPLC-UV calibrated with known solutions of scaffolds.
23. Arumugam, V.; Routledge, A.; Abell, C.; Balasubramanian, S. Tetrahedron Lett. 1997, 38, 6473-6476.
24. Hari, A.; Benjamin, L. M. Tetrahedron Lett. 1999, 40, 245-248.
25. Gary, B. P.; Guo, P. W. Tetrahedron Lett. 1996, 37, 4887-4890.
26. After 48 h only 3.5% of the nitro compound has been converted to the amine according to HPLC at 254 nm.
27. Pei, Y.; Houghten, R. A.; Kiely, J. S. Tetrahedron Lett. 1997, 38, 3349-3352.
28. 1H NMR using hexamethyldisiloxane as an internal standard showed no cleavage within the method's accuracy limits (approximately 5%).
29. Analysis was made using a 4.5 cm HPLC column with a 2 min solvent gradient.
30. Analysis was made using a 20 cm HPLC column with a 4 min solvent gradient.
31. Olsson, T.; Shcherbukhin, V. Synthesis and Structure Administrator (SaSA), 1997; http://www.astrazeneca.com.
32. Sadowski, J.; Kubinyi, H. A Scoring Scheme for Discriminating between Drugs and Nondrugs. J. Med. Chem. 1998, 41, 3325-3329.
33. Ajay, W.; Walters, P.; Murcko, M. A. Can We Learn To Distinguish Between "Drug-like" and "Nondrug-like" Molecules? J. Med. Chem. 1998, 41, 3314-3324.
34. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.
35. Daylight Users Manual, Release 4.41; Daylight Chemical Information Systems, Inc.: Irvine, CA, 1992-95; http:// www.daylight.com.
36. Oprea, T. I. Property distribution of drug-related chemical databases. J. Comput.-Aided Mol. Des. 2000, 14, 251-264.
37. Oprea, T. I.; Gottfries, J.; Sherbuhin, V.; Svensson, P.; Kühler, T. C. Chemical information management in drug discovery: Optimizing the computational and combinatorial chemistry interfaces. J. Mol. Graphics Modell. 2000, 18, 512-524.
38. Available from MDL Information Systems, http://www.m-dli.com/dats/pharmdb.html. The ACD database is a compilation of over 300 000 commercially available substances from over 500 catalogs worldwide.
39. CLOGP is available from Biobyte Corporation, Claremont, CA, http://www.biobyte.com/bb/prod/clogp40.html.
40. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. I. The Design of Leadlike Combinatorial Libraries Angew. Chem. Int. Ed. 1999, 38, 3743-3748; German version: Angew. Chem. 1999, 111, 3962-3967.
41. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. I. The Design of Leadlike Combinatorial Libraries Angew. Chem. Int. Ed. 1999, 38, 3743-3748; German version: Angew. Chem. 1999, 111, 3962-3967.
42. A total of 65 mg resin/reservoir for the m-regioisomers and 56 mg resin/well for the o-regioisomers, which corresponds to approximately 30 μmol/reservoir.
43. 1H NMR spectra due to the existence of rotamers for these compounds.