Novel sulfone-containing di- and trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 13, 2009, Pages 3418-3422

  Cherney, Robert J ^a   Mo, Ruowei ^a   Meyer, Dayton T ^a   Voss, Matthew E ^a   Lo, Yvonne C ^a   Yang, Gengjie ^a   Miller, Persymphonie B ^a   Scherle, Peggy A ^a   Tebben, Andrew J ^a   Carter, Percy H ^a   Decicco, Carl P ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

CCR2; CCR2 antagonist; Chemokine; GPCR

Indexed keywords

CALCIUM; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; CYCLOHEXANE DERIVATIVE; ISOPROPYLMETHYLCYCLOHEXYLSULFONE DERIVATIVE; SULFONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CALCIUM TRANSPORT; CHEMOTAXIS; CONFORMATION; DRUG SYNTHESIS; IC 50; IMMUNOMODULATION; NONHUMAN; SUBSTITUTION REACTION;

CYCLOHEXANES; MOLECULAR CONFORMATION; RECEPTORS, CCR2; SULFONES;

EID: 66349121609     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.041     Document Type: Article

References (25)

1. D'Elios M.M., Del Prete G., and Amedei A. Expert Opin. Ther. Patents 18 (2008) 309
2. Horuk R. ScientificWorldJournal 7 (2007) 224
3. Charo I.F., and Ransohoff R.M. N. Eng. J. Med. 354 (2006) 610
4. Gerard C., and Rollins B.J. Nat. Immunol. 2 (2001) 108
5. Daly C., and Rollins B.J. Microcirculation 10 (2003) 247
6. 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
7. Feria M., and Diaz-Gonzalez F. Expert Opin. Ther. Patents 16 (2006) 49
8. Tak P.P. Best Pract. Res. Clin. Rheumatol. 20 (2006) 929
9. Coll B., Alonso-Villaverde C., and Joven J. Clin. Chim. Acta 383 (2007) 21
10. Peters W., and Charo I.F. Curr. Opin. Lipidol. 12 (2001) 175
11. Mahad D.J., and Ransohoff R.M. Semin. Immunol. 15 (2003) 23
12. 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
13. Carter P.H., Cherney R.J., and Mangion I.K. Annu. Rep. Med. Chem. 42 (2007) 211
14. Dawson J., Miltz W., Mir A.K., and Wiessner C. Expert Opin. Ther. Targets 7 (2003) 35
15. 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
16. Nakagawa I., and Hata T. Tetrahedron Lett. 17 (1975) 1409
17. Majer P., and Randad R.S. J. Org. Chem. 59 (1994) 1937
18. Chini M., Crotti P., Flippin L.A., and Macchia F. J. Org. Chem. 55 (1990) 4265
19. Marczak S., and Wicha J. Synth. Commun. 20 (1990) 1511
20. Williams D.R., Brown D.L., and Benbow J.W. J. Am. Chem. Soc. 111 (1989) 1923
21. Carter, P. H.; Cherney, R. J. WO 2002050019, 2002.
22. 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
23. 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.
24. Cherney R.J., Brogan J.B., Mo R., Lo Y.C., Yang G., Miller P.B., Scherle P.A., Molino B.F., Carter P.H., and Decicco C.P. Bioorg. Med. Chem. Lett. 19 (2009) 597
25. * level of theory from optimized conformations at that level using the program qchem (Q-Chem Inc, Pittsburgh, PA). The lower energy conformer from each pair was arbitrarily set to 0 kcal/mol and the energy of the other conformer reported relative to it.