Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 4, 2004, Pages 941-945

  Shen, Dong Ming ^a   Shu, Min ^a   Willoughby, Christopher A ^a   Shah, Shrenik ^a   Lynch, Christopher L ^a   Hale, Jeffrey J ^a   Mills, Sander G ^a   Chapman, Kevin T ^a   Malkowitz, Lorraine ^a   Springer, Martin S ^a   Gould, Sandra L ^a   DeMartino, Julie A ^a   Siciliano, Salvatore J ^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

ACETIC ACID; ACETIC ACID DERIVATIVE; ALKYL GROUP; ALPHA (PYRROLIDIN 1 YL)ACETIC ACID; ANTIVIRUS AGENT; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; PALLADIUM; PHENYL GROUP; PIPERIDINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRROLIDINE DERIVATIVE; SILVER DERIVATIVE; TRIFLUOROMETHANESULFONIC ACID; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; BIOAVAILABILITY; CONTROLLED STUDY; DEALKYLATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; IC 50; IN VITRO STUDY; NONHUMAN; STRUCTURE ANALYSIS;

ANIMALIA; HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 10744230147     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.12.005     Document Type: Article

References (29)

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 paper in this issue. doi:10.1016/j.bmcl.2003.12.004.
14. This trend was not always observed. In the related 4-(3-phenylpropyl) piperidine series, the isopropyl compound has similar pharmacokinetic profile as the cyclohexyl compound with diminished CCR5 binding and antiviral activities (ref 5).
15. Siciliano S.J., Kuhmann S.E., Weng Y., Madani N., Springer M.S., Lineberger J.E., Danzeisen R., Miller M.D., Kavanaugh M.P., DeMartino J.A., Kabat D. J. Biol. Chem. 274:1999;1905.
16. 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.
17. 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.
18. See note 20 of ref 3 for assay protocol.
19. We have not studied the mechanism or scope of this transformation, although it appears to be general to compounds reported here. During a discussion with Prof. Barry M. Trost, he suggested a Pd-mediated oxidative decarboxylation of compounds such as 1 and 9 to an iminium intermediate followed by hydrolysis as a possible pathway.
20. Boto A., Hernandez R., Suarez E. J. Org. Chem. 65:2000;4930. and references cited therein.
21. Barsukov A.V., Yaroshenko G.F., Lastovskii R.P., Dyatlova N.M. J. Gen. Chem. USSR (Engl. Transl.). 53:1983;1109.
22. Hashiguchi S., Maeda Y., Kishimoto S., Ochiai M. Heterocycles. 24:1986;2273.
23. Gangopadhyay S., Ali M., Saha S.K., Banerjee P. J. Chem. Soc., Dalton Trans. 1991;2729.
24. Carrell, D. P.; Cragoe, E. J. WO 9640104, 1996.
25. Guziec F.S.J., Torres F.F. J. Org. Chem. 58:1993;1604.
26. Kahovec L., Hohlrausch K.W.F. Monatsh. Chem. 74:1943;104.
27. 2O/toluene with or without sonication gave much lower conversions. Silver trifluoroacetate gave similar results as silver triflate.
28. Petit Y., Larcheveque M. Org. Synth. 75:1997;37.
29. About 2-fold excess of 15 was used to minimize the bis-alkylation product discussed in footnote 27 above.