Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 4, 2004, Pages 947-952

  Shu, Min ^a   Loebach, Jennifer L ^a   Parker, Kerry A ^a   Mills, Sander G ^a   Chapman, Kevin T ^a   Shen, Dong Ming ^a   Malkowitz, Lorraine ^a   Springer, Martin S ^a   Gould, Sandra L ^a   DeMartino, Julie A ^a   Siciliano, Salvatore J ^a   Di Salvo, Jerry ^a   Lyons, Kathy ^a   Pivnichny, James V ^a   Kwei, Gloria Y ^a   Carella, Anthony ^a   Carver, Gwen ^a   Holmes, Karen ^a   Schleif, William A ^a   Danzeisen, Renee ^a   Hazuda, Daria ^a   Kessler, Joseph ^a   Lineberger, Janet ^a   Miller, Michael D ^a   Emini, Emilio A ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Antiviral; CCR5 antagonist; HIV 1; Pyrazole

Indexed keywords

ANTIVIRUS AGENT; BENZYL DERIVATIVE; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; PHENYL GROUP; PIPERIDINE DERIVATIVE; PYRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; HELA CELL; HUMAN; HUMAN CELL; HYDROPHILICITY; LIPOPHILICITY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 10744226269     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.12.006     Document Type: Article

References (25)

1. Finke P.E., Oates B., Mills S.G., MacCoss M., Malkowitz L., Springer M.S., Gould S.L., DeMartino J.A., Carella A., Carver G., Holmes K., Danzeisen R., Hazuda D., Kessler J., Lineberger J., Miller M., Schlief W.A., Emini E.A. Bioorg. Med. Chem. Lett. 11:2001;2475. and references cited therein.
2. Willoughby C.W., Berk S.C., Rosauer K.G., Delgrado S., Chapman K.T., Gould S.L., Springer M.S., Malkowitz L., Schlief W.A., Hazuda D., Miller M., Kessler J., Danzeisen R., Holmes K., Lineberger J., Carella A., Carver G., Emini E.A. Bioorg. Med. Chem. Lett. 11:2001;3137.
3. Hale J.J., Budhu R.J., Mills S.G., MacCoss M., Malkowitz L., Siciliano S., Gould S.L., DeMartino J.A., Springer M.S. Bioorg. Med. Chem. Lett. 11:2001;1437.
4. Hale J.J., Budhu R.J., Holson E.B., Finke P.E., Oates B., Mills S.G., MacCoss M., Gould S.L., DeMartino J.A., Springer M.S., Siciliano S., Malkowitz L., Schlief W.A., Hazuda D., Miller M., Kessler J., Danzeisen R., Holmes K., Lineberger J., Carella A., Carver G., Emini E.A. Bioorg. Med. Chem. Lett. 11:2001;2741.
5. Lynch C.L., Hale J.J., Budhu R.J., Gentry A.L., Mills S.G., Chapman K.T., MacCoss M., Malkowitz L., Springer M.S., Gould S.L., DeMartino J.A., Siciliano S.J., Cascieri M.A., Carella A., Carver G., Holmes K., Schlief W.A., Danzeisen R., Hazuda D., Kessler J., Lineberger J., Miller M., Emini E.A. Bioorg. Med. Chem. Lett. 12:2002;3001. and references cited therein.
6. Willoughby C.W., Rosauer K.G., Hale J.J., Budhu R.J., Mills S.G., Chapman K.T., MacCoss M., Malkowitz L., Springer M.S., Gould S.L., DeMartino J.A., Siciliano S.J., Cascieri M.A., Carella A., Carver G., Holmes K., Schlief W.A., Danzeisen R., Hazuda D., Kessler J., Lineberger J., Miller M., Emini E.A. Bioorg. Med. Chem. Lett. 13:2003;427.
7. Lynch C.L., Willoughby C.W., Hale J.J., Holson E.J., Budhu R.J., Gentry A.L., Rosauer K.G., Caldwell C.G., Chen P., Mills S.G., MacCoss M., Berk S., Chen L., Chapman K.T., Malkowitz L., Springer M.S., Gould S.L., DeMartino J.A., Siciliano S.J., Cascieri M.A., Carella A., Carver G., Holmes K., Schlief W.A., Danzeisen R., Hazuda D., Kessler J., Lineberger J., Miller M., Emini E.A. Bioorg. Med. Chem. Lett. 13:2003;119.
8. Baba M., Nishimura O., Kanzaki N., Okamoto M., Sawada H., Iizawa Y., Shiraishi M., Aramaki Y., Okonogi K., Ogawa Y., Meguro K., Fujino M. Proc. Natl. Acad. Sci. U.S.A. 96:1999;5698.
9. Tagat J.R., Steensma R.W., McCombie S.W., Nazareno D.V., Lin S.-I., Neustadt B.R., Cox K., Xu S., Wojcik L., Murray M.G., Vantuno N., Baroudy B.M., Strizki J.M. J. Med. Chem. 44:2001;3343. and references cited therein.
10. For a review, see: Kazmierski W., Bifulco N., Yang H., Boone L., DeAnda F., Watson C., Kenakin T. Bioorg. Med. Chem. 11:2003;2663.
11. Lynch C.L., Gentry A.L., Hale J.J., Mills S.G., MacCoss M., Malkowitz L., Springer M.S., Gould S.L., DeMartino J.A., Siciliano S.J., Cascieri M.A., Doss G., Carella A., Carver G., Holmes K., Schlief W.A., Danzeisen R., Hazuda D., Kessler J., Lineberger J., Miller M., Emini E.A. Bioorg. Med. Chem. Lett. 12:2002;677.
12. Kim D., Wang L., Caldwell C.G., Chen P., Finke P.E., Oates B., MacCoss M., Mills S.G., Malkowitz L., Gould S.L., DeMartino J.A., Springer M.S., Hazuda D., Miller M., Kessler J., Danzeisen R., Carver G., Carella A., Holmes K., Lineberger J., Schlief W.A., Emini E.A. Bioorg. Med. Chem. Lett. 11:2001;3099. and 3103.
13. Shen, D.-M.; Shu, M.; Mills, S. G.; Chapman, K. T.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; Kwei, G. Y.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A. Bioorg. Med. Chem. Lett. 2004, 14, preceding ref 14 in this issue. doi:10.1016/j.bmcl.2003.12.004.
14. Shen, D.-M.; Shu, M.; Willoughby, C. W.; Shah, S.; Lynch, C. L.; Hale, J. J.; Mills, S. G.; Chapman, K. T.; Malkowitz, L.; Springer, M. S.; Gould, S. L. ; DeMartino, J. A.; Siciliano, S. J.; Lyons, K.; Pivnichny, J. V.; Kwei, G. Y.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A. Bioorg. Med. Chem. Lett. 2004, 14, preceding paper in this issue. doi:10.1016/j.bmcl.2003.12.005.
15. Corey E.J., Fuchs P.L. Tetrahedron Lett. 13:1972;3769.
16. Waner B.P., Buchwald S.L. J. Org. Chem. 5:1994;5822.
17. Logue M.W., Teng K. J. Org. Chem. 47:1982;2549.
18. For the preparation of 8 and its p-methoxybenzyl analogues, see ref 5 and 14 above.
19. Hazuda D.J., Felock P., Witmer M., Wolfe A., Stillmock K., Grobler J.A., Espeseth A., Gabryelski L., Schleif W., Blau C., Miller M.D. Science. 287:2000;646.
20. Inhibition of radio-labeled MK-499 binding using human embryonic kidney (HEK) cells expressing hERG. For procedure, see: Wang J., Della Penna K., Wang H., Karczewski J., Connolly T.M., Koblan K.S., Bennett P.B., Salata J.J. Am. J. Physiol.-Heart Circ. Physiol. 284:2003;H256.
21. Crumb W., Cavero I. Pharm. Sci. Technol. Today. 2:1999;270.
22. Fermini B., Fossa A.A. Nat. Rev. Drug Discov. 2:2003;439.
23. The structures of 9b and 9c are:
24. + channel activity compared to 9b and 9d, respectively.
25. Saag M.S., Emini E.A., Laskin O.L., Douglas J., Lapidus W.I., Schleif W.A., Whitley R.J., Hildebrand C., Byrnes V.W., Kappes J.C., Anderson K.W., Massari F.E., Shaw G.M. New Engl. J. Med. 329:1993;1065.