Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 9, 2012, Pages 3311-3316

  Carter, Percy H ^a   Brown, Gregory D ^a   King, Sarah R ^a   Voss, Matthew E ^a   Tebben, Andrew J ^a   Cherney, Robert J ^a   Mandlekar, Sandhya ^a   Lo, Yvonne C ^a   Yang, Gengjie ^a   Miller, Persymphonie B ^a   Scherle, Peggy A ^a   Zhao, Qihong ^a   Decicco, Carl P ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

CCR2; Chemokine; GPCR; Isostere

Indexed keywords

AMINOALCOHOL; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; CYCLIC AMP; DIAMINE;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CALCIUM TRANSPORT; CHEMICAL MODIFICATION; CHEMOTAXIS; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG SYNTHESIS; MONOCYTE; MOUSE; NONHUMAN; RECEPTOR BINDING; STEREOCHEMISTRY;

AMINO ALCOHOLS; ANIMALS; BIOLOGICAL AVAILABILITY; MICE; RECEPTORS, CCR2;

MURINAE;

EID: 84859863823     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.03.007     Document Type: Article

References (23)

1. S. Gordon, and P.R. Taylor Nat. Rev. Immunol. 5 2005 953
2. Y.S. Kang, J.Jo. Cha, Y.Y. Hyun, and D.R. Cha Expert Opin. Investig. Drugs 20 2011 745
3. I.F. Charo, and R.M. Ransohoff N. Engl. J. Med. 354 2006 610
4. M. Feria, and F. Díaz-González Exp. Opin. Ther. Patents 16 2006 49
5. P.H. Carter, R.J. Cherney, and I.K. Mangion Annu. Rep. Med. Chem. 42 2007 211
6. M. Xia, and Z. Sui Exp Opin Ther Pat. 19 2009 295
7. M. Struthers, and A. Pasternak Curr. Top. Med Chem. 10 2010 1278
8. T.J. Schall, and A.E.I. Proudfoot Nat. Rev. Immunol. 11 2011 355
9. R. Horuk Nat. Rev. Drug Disc. 8 2009 23
10. R.J. Cherney, R. Mo, D.T. Meyer, M.E. Voss, Y.C. Lo, G. Yang, P.B. Miller, P.A. Scherle, A.J. Tebben, P.H. Carter, and C.P. Decicco Bioorg. Med. Chem. Lett. 19 2009 3418
11. P.H. Carter, G.D. Brown, S.R. Friedrich, R.J. Cherney, A.J. Tebben, Y.C. Lo, G. Yang, H. Jezak, K.A. Solomon, P.A. Scherle, and C.P. Decicco Bioorg. Med. Chem. Lett. 17 2007 5455
12. A. Alex, D.S. Millan, M. Perez, F. Wakenhut, and G.A. Whitlock MedChemCommun 2 2011 669
13. For the details on the biological assays and on the synthesis of compounds 1-26, 28, and 48-50, see: Carter, P.; Cherney, R. J. PCT Int. Appl. WO 2002050019.
14. R.J. Smith, M. Trzoss, M. Buhl, and S. Bienz Eur. J. Org. Chem. 2002 2770
15. Z. Czajgucki, P. Sowinski, and R. Andruszkiewicz Amino Acids 24 2003 289
16. M.M. Midland, D.C. McDowell, R.L. Hatch, and A. Tramontano J. Am. Chem. Soc. 102 1980 867
17. R.J. Cherney, R. Mo, D.T. Meyer, D.J. Nelson, Y.C. Lo, G. Yang, P.A. Scherle, S. Mandlekar, Z.R. Wasserman, H. Jezak, K.A. Solomon, A.J. Tebben, P.H. Carter, and C.P. Decicco J. Med. Chem. 51 2008 721
18. G.V. De Lucca, U.T. Kim, B.J. Vargo, J.V. Duncia, J.B.I.I.I. Santella, D.S. Gardner, C. Zheng, A. Liauw, Z. Wang, G. Emmett, D.A. Wacker, P.K. Welch, M. Covington, N.C. Stowell, E.A. Wadman, A.M. Das, P. Davies, S. Yeleswaram, D.M. Graden, K.A. Solomon, R.C. Newton, G.L. Trainor, C.P. Decicco, and S.S. Ko J. Med. Chem. 48 2005 2194
19. 3; and aq LiOH, MeOH. For details, see: Carter, P. H.; Cherney, R. J.; Batt, D. G.; Brown, G. D.; Duncia, J. V.; Gardner, D. S.; Yang, M. G. PCT Intl. Appl. WO 2005020899.
20. Other investigators have also recently reported the synthesis of CCR2 antagonists containing indazoles. See: X. Zhang, H. Hufnagel, C. Hou, E. Opas, S. McKenney, C. Crysler, J. O'Neill, D. Johnson, and Z. Sui Bioorg. Med. Chem. Lett. 21 2011 6042
21. Compounds 29-47 are all described in Carter, P. PCT Int. Appl. WO 2004098512.
22. Compounds 51 - 53 were synthesized as described in Carter, P.; Voss, M. E. PCT Int. Appl. WO 2004071449. Compound 54 was made by analogy, using R-Methionine.
23. R.J. Cherney, R. Mo, D.T. Meyer, M.E. Voss, M.G. Yang, J.B. Santella 3rd, J.V. Duncia, Y.C. Lo, G. Yang, P.B. Miller, P.A. Scherle, Q. Zhao, S. Mandlekar, M.E. Cvijic, J.C. Barrish, C.P. Decicco, and P.H. Carter Bioorg. Med. Chem. Lett. 20 2010 2425