Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 4, 2003, Pages 705-708

  Palani, Anandan ^a   Shapiro, Sherry ^a   Clader, John W ^a   Greenlee, William J ^a   Blythin, David ^a   Cox, Kathleen ^a   Wagner, Nicole E ^a   Strizki, Julie ^a   Baroudy, Bahige M ^a   Dan, Niya ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; CHEMOKINE RECEPTOR CCR5;

ARTICLE; DRUG BIOAVAILABILITY; DRUG SCREENING; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY;

EID: 0037295050     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)01062-4     Document Type: Article

References (23)

1. (a) Littman D.R. Cell. 93:1998;677
2. (b) Murphy P.M. Nature Immun. 2:2001;116
3. (c) Hunt S.W. III, LaRosa G.J. Ann. Rep. Med. Chem. 33:1998;263
4. (d) Saunders J., Tarby C.M. Drug Discov. Today. 4:1999;80.
5. Berger E.A., Murphy P.M., Farber J.M. Annu. Rev. Immunol. 17:1999;657.
6. (a) Cocchi F., DeVico A.L., Garzino-Demo A., Arya S.K., Gallo R.C., Lusso P. Science. 270:1995;1811
7. (b) Michael N.L., Moore J.P. Nat. Med. 5:1999;740.
8. (a) Samson M., Libert F., Doranz B.J., Rucker J., Liesnard C., Farber C.-M., Saragosti S., Lapoumeroulle C., Cognaux J., Forceille C., Muyldermans G., Vehofstede C., Butonboy G., Georges M., Imai T., Rana S., Yi Y., Smyth R.J., Collman R.G., Doms R.W., Vassart G., Parmentier M. Nature. 382:1996;722
9. (b) Liu R., Paxton W.A., Choe S., Ceradini D., Martin S.R., Horuk R., MacDonald M.E., Stuhlmann H., Koup R.A., Landau N.R. Cell. 86:1996;367.
10. Michael N.L., Chang G., Louie L.G., Mascola J.R., Dondero D., Birx D.L., Sheppard H.W. Nature Med. 3:1997;338.
11. (a) Mastrolorenzo A., Scozzafava A., Supuran C.T. J. Enz. Inh. and Med. Chem. 17:2002;69
12. (b) Mastrolorenzo A., Scozzafava A., Supuran C.T. Expert Opin. Ther. Patents. 11:2001;1245. and references sited therein.
13. (a) Palani A., Shapiro S., Josien H., Bara T., Clader J.W., Greenlee W.J., Cox K., Strizki J., Enders M., Baroudy B.M. J. Med. Chem. 45:2002;3143
14. (b) Palani A., Shapiro S., Clader J.W., Greenlee W.J., Cox K., Strizki J., Endres M., Baroudy B.M. J. Med. Chem. 44:2001;3339
15. (c) Strizki J.M., Xu S., Wagner N.E., Wojcik L., Liu J., Hou Y., Endres M., Palani A., Shapiro S., Clader J.W., Greenlee Tagat J.R., McCombie S., Cox K., Fawzi A.B., Chou C.C., Pugliese-Sivo C., Davies L., Moreno M.E., Ho D.D., Trkola A., Stoddart C.A., Moore J.P., Reyes G.R., Baroudy B.M. Proc. Natl. Acad. Sci. 98:2001;12718.
16. Baroudy, B. In AIDS - 14th International Conference (Part I), New Drugs, New Targets Symposium, Barcelona, Spain, July 7-12, 2002.
17. (a). For other reports on the observation of rotamers, see: Bastiaansen L.A.M., Kanters J.A., van der Steen F.H., de Graaf J.A.C., Buck H.M.J. Chem. Soc., Chem. Commun. 1986;536
18. (b) Ikeura Y., Ishichi Y., Tanaka T., Fujishima A., Murabayashi M., Kawada M., Ishimaru T., Kamo I., Doi T., Natsugari H. J. Med. Chem. 41:1998;4232
19. (c) Clayden J., Johnson P., Pink J.H., Helliwell M.J. Org. Chem. 65:2000;7033
20. (d) Ates A., Curran D.P. J. Am. Chem. Soc. 123:2001;5130.
21. The equilibrium half-life for interconversion between rotamers 2 and 3 (A) to 4 and 5 (B) in rat plasma is 1.5 h. The equilibrium end point is 60% A: 40% B.
22. 50 values represent the concentration of compound required to inhibit luciferase production by 50% compared with control cultures. For a description of all original or typical bio-assays, see ref 7b.
23. The number given for rotamers 2-5 in Figure 3 is arbitrary and does not correspond to fractions isolated from HPLC. The structural assignments were not carried out for compounds 2-5.