Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 3, 2009, Pages 597-601

  Cherney, Robert J ^a   Brogan, John B ^b   Mo, Ruowei ^a   Lo, Yvonne C ^a   Yang, Gengjie ^a   Miller, Persymphonie B ^a   Scherle, Peggy A ^a   Molino, Bruce F ^b   Carter, Percy H ^a   Decicco, Carl P ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

CCR2 antagonist; Chemokines; MCP 1

Indexed keywords

CALCIUM; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR2; CYCLOHEXANE DERIVATIVE;

ARTICLE; CALCIUM TRANSPORT; CHEMOTAXIS; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; IC 50; RECEPTOR AFFINITY;

BINDING SITES; CALCIUM; CHEMISTRY, PHARMACEUTICAL; CHEMOKINE CCL2; CHEMOTAXIS; CYCLOHEXANES; DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PROTEIN BINDING; RECEPTORS, CCR2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 58549103078     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.12.062     Document Type: Article

References (21)

1. D'Elios M.M., Del Prete G., and Amedei A. Expert Opin. Ther. Patents 18 (2008) 309
2. Horuk R. Sci. World J. 7 (2007) 224
3. Charo I.F., and Ransohoff R.M. N Eng. J. Med. 354 (2006) 610
4. For chemokine nomenclature, see:. Murphy P.M., Baggiolini M., Charo I.F., Hebert C.A., Horuk R., Matsushima K., Miller L.H., Oppenheim J.J., and Power C.A. Pharmacol. Rev. 52 (2000) 145
5. Daly C., and Rollins B.J. Microcirculation 10 (2003) 247
6. Feria M., and Diaz-Gonzalez F. Expert Opin. Ther. Patents 16 (2006) 49
7. Tak P.P. Best Pract. Res. Clin. Rheumatol. 20 (2006) 929
8. Coll B., Alonso-Villaverde C., and Joven J. Clin. Chim. Acta 383 (2007) 21
9. Peters W., and Charo I.F. Curr. Opin. Lipidol. 12 (2001) 175
10. Mahad D.J., and Ransohoff R.M. Semin. Immunol. 15 (2003) 23
11. Kamei N., Tobe K., Suzuki R., Ohsugi M., Watanabe T., Kubota N., Ohtsuka-Kowatari N., Kumagai K., Sakamoto K., Kobayashi M., Yamauchi T., Ueki K., Oishi Y., Nishimura S., Manabe I., Hashimoto H., Ohnishi Y., Ogata H., Tokuyama K., Tsunoda M., Ide T., Murakami K., Nagai R., and Kadowaki T. J. Biol. Chem. 281 (2006) 26602
12. Carter, P. H.; Cherney, R. J.; Mangion, I. K. Annual Reports in Medicinal Chemistry. 2007, 42, 211.
13. Dawson J., Miltz W., Mir A.K., and Wiessner C. Expert Opin. Ther. Targets 7 (2003) 35
14. Cherney R.J., Mo R., Meyer D.T., Nelson D.J., Lo Y.C., Yang G., Scherle P.A., Mandlekar S., Wasserman Z.R., Jezak H., Solomon K.A., Tebben A.J., Carter P.H., and Decicco C.P. J. Med. Chem. 51 (2008) 721
15. Cherney R.J., Nelson D.J., Lo Y.C., Yang G., Scherle P.A., Jezak H., Solomon K.A., Carter P.H., and Decicco C.P. Bioorg. Med. Chem. Lett. 18 (2008) 5063
16. Fletcher S.R., Baker R., Chambers M.S., Herbert R.H., Hobbs S.C., Thomas S.R., Verrier H.M., Watt A.P., and Ball R.G. J. Org. Chem. 59 (1994) 1771
17. Chini M., Crotti P., Flippin L.A., and Macchia F. J. Org. Chem. 56 (1991) 7043
18. Carter, P. H.; Cherney, R. J. Diamines as modulators of chemokine receptor activity. WO 2002050019, 2002.
19. Wacker D.A., Santella III J.B., Gardner D.S., Varnes J.G., Estrella M., DeLucca G.V., Ko S.S., Tanabe K., Watson P.S., Welch P.K., Covington M., Stowell N.C., Wadman E.A., Davies P., Solomon K.A., Newton R.C., Trainor G.L., Friedman S.M., Decicco C.P., and Duncia J.V. Bioorg. Med. Chem. Lett. 12 (2002) 1785
20. For all compounds tested in the calcium flux assay, calcium flux inhibition was unchanged when the compound was incubated alone (without MCP-1 present), thus validating the compound as an antagonist and not a partial agonist.
21. Carter P.H., Brown G.D., Friedrich S.R., Cherney R.J., Tebben A.J., Lo Y.C., Yang G., Jezak H., Solomon K.A., Scherle P.A., and Decicco C.P. Bioorg. Med. Chem. Lett. 17 (2007) 5455