Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 24, 2010, Pages 7473-7478

  Xue, Chu Biao ^a   Wang, Anlai ^a   Meloni, David ^a   Zhang, Ke ^a   Kong, Ling ^a   Feng, Hao ^a   Glenn, Joseph ^a   Huang, Taisheng ^a   Zhang, Yingxin ^a   Cao, Ganfeng ^a   Anand, Rajan ^a   Zheng, Changsheng ^a   Xia, Michael ^a   Han, Qi ^a   Robinson, D J ^a   Storace, Lou ^a   Shao, Lixin ^a   Li, Mei ^a   Brodmerkel, Carrie M ^a   Covington, Maryanne ^a   Scherle, Peggy ^a   Diamond, Sharon ^a   Yeleswaram, Swamy ^a   Vaddi, Kris ^a   Newton, Robert ^a   Hollis, Greg ^a   Friedman, Steven ^a   Metcalf, Brian ^a   more..

^a Experimental Station   (United States)

Author keywords

Antagonist; Chemokine; Human CCR2; Murine CCR2

Indexed keywords

CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR2; INCB 3344; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG SYNTHESIS; HUMAN; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; DRUG EVALUATION, PRECLINICAL; HUMANS; MICE; PROTEIN BINDING; PYRROLIDINES; RATS; RECEPTORS, CCR2; STRUCTURE-ACTIVITY RELATIONSHIP;

MURINAE; MUS; RODENTIA;

EID: 78549245467     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.020     Document Type: Article

References (39)

1. R.W. Kinne, R. Brauer, B. Stuhlmuller, E. Palombo-Kinne, and G. Burmester Arthritis Res. 2 2000 189
2. P. Barrera, A. Blom, P.L. van Lent, L. van Bloois, J.H. Beijnen, N. van Rooiken, M.C. de Waal Malefijt, L.B. van de Putte, and W.B. van den Berg Arthritis Rheum. 43 2000 1951
3. K.J. Katschke Jr., J.B. Rottman, J.H. Ruth, S. Qin, L. Wu, G. LaRosa, P. Ponath, C.C. Park, R.M. Pope, and A.E. Koch Arthritis Rheum. 44 2001 1022
4. C.A. Power, and A.E. Proudfoot Curr. Opin. Pharmacol. 1 2001 417
5. B. Lu, B.J. Rutledge, L. Gu, J. Fiorillo, N.W. Lukacs, S.L. Kunkel, R. North, C. Gerard, and B.J. Rollins J. Exp. Med. 187 1998 601
6. W.A. Kuziel, S.J. Morgan, T.C. Dawson, S. Griffin, O. Smithies, K. Ley, and N. Maeda Proc. Natl. Acad. Sci. U.S.A. 94 1997 12053
7. T. Kurihara, G. Warr, J. Loy, and R. Bravo J. Exp. Med. 186 1997 1757
8. L. Boring, J. Gosling, S.W. Chensue, S.L. Kunkel, R.V. Farese, H.E. Broxmeyer, and I.F. Charo J. Clin. Invest. 100 1997 2552
9. J.H. Gong, L.G. Ratkay, J.D. Waterfield, and I. ClarkLewis J. Exp. Med. 186 1997 131
10. H. Ogata, M. Takeya, T. Yoshimura, K. Takagi, and K. Takahashi J. Pathol. 182 1997 106
11. D.R. Huang, J.T. Wang, P. Kivisakk, B.J. Rollins, and R.M. Ransohoff J. Exp. Med. 193 2001 713
12. L. Izikson, R.S. Klein, I.F. Charo, H.L. Weiner, and A.D. Luster J. Exp. Med. 192 2000 1075
13. B.T. Fife, G.B. Huffnagle, W.A. Kuziel, and W.J. Karpus J. Exp. Med. 192 2000 899
14. T.C. Dawson, W.A. Kuziel, T.A. Osahar, and N. Maeda Atherosclerosis 143 1999 205
15. L. Gu, Y. Okada, S.K. Clinton, C. Gerard, G.K. Sukhova, P. Libby, and B.J. Rollins Mol. Cell 2 1998 275
16. C. Daly, and B.J. Rollins Microcirculation 10 2003 247
17. C. Abbadie, J.A. Lindia, A.M. Cumiskey, L.B. Peterson, J.S. Mudgett, E.K. Bayne, J.A. DeMartino, D.E. MacIntyre, and M.J. Forrest Proc. Natl. Acad. Sci. U.S.A. 100 2003 7947
18. G. Van Lommen, J. Doyon, E. Coesemans, S. Boeckx, M. Cools, M. Buntinx, B. Hermans, and J. VanWauwe Bioorg. Med. Chem. Lett. 15 2005 497
19. L. Yang, C. Zhou, L. Guo, G.J. Morriello, G. Butora, A. Pasternak, W.H. Parsons, S.G. Mills, M. MacCoss, P.P. Vicario, H. Zweerink, J.M. Ayala, S. Goyal, W.A. Hanlon, M.A. Cascieri, and M.S. Springer Bioorg. Med. Chem. Lett. 16 2006 3735
20. G. Butora, G.J. Morriello, S. Kothandaraman, D. Guiadeen, A. Pasternak, W.H. Parsons, M. MacCoss, P.P. Vicario, M.A. Cascieri, and L. Yang Bioorg. Med. Chem. Lett. 16 2006 4715
21. A. Pasternak, D. Marino, P.P. Vicario, J.M. Ayala, M.A. Cascierri, W. Parsons, S.G. Mills, M. MacCoss, and L. Yang J. Med. Chem. 49 2006 4801
22. C. Zhou, L. Guo, W.H. Parsons, S.G. Mills, M. MacCoss, P.P. Vicario, H. Zweerink, M.A. Cascieri, M.S. Springer, and L. Yang Bioorg. Med. Chem. Lett. 17 2007 309
23. A.B. Pinkerton, D. Huang, R.V. Cube, J.H. Hutchinson, M. Struthers, J.M. Ayala, P.P. Vicario, S.R. Patel, T. Wisniewski, J.A. DeMartino, and J.-M. Vernier Bioorg. Med. Chem. Lett. 17 2007 807
24. G. Butora, R. Jiao, W.H. Parsons, P.P. Vicario, H. Jin, J.M. Ayala, M.A. Cascieri, and L. Yang Bioorg. Med. Chem. Lett. 17 2007 3636
25. B. Lagu, C. Gerchak, M. Pan, C. Hou, M. Singer, R. Malaviya, M. Matheis, G. Olini, D. Cavender, and M. Wachter Bioorg. Med. Chem. Lett. 17 2007 4382
26. 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
27. M. Xia, C. Hou, S. Pollack, J. Brackley, D. DeMong, M. Pan, M. Singer, M. Matheis, G. Olini, D. Cavender, and M. Wachter Bioorg. Med. Chem. Lett. 17 2007 5964
28. L. Yang, G. Butora, R.X. Jiao, A. Pasternak, C. Zhou, W.H. Parsons, S.G. Mills, P.P. Vicario, J.M. Ayala, M.A. Cascieri, and M. MacCoss J. Med. Chem. 50 2007 2609
29. M. Xia, C. Hou, D.E. DeMong, S.R. Pollack, M. Pan, J.A. Brackley, N. Jain, C. Gerchak, M. Singer, R. Malaviya, M. Matheis, G. Olini, D. Cavender, and M. Wachter J. Med. Chem. 50 2007 5561
30. Tarby, C. M.; Endo, N.; Moree, W. J.; Kataoka, K.; Ramirez-Weinhouse, M. M.; Imai, M.; Bradley, E.; Saunders, J.; Kato, Y.; Myers, P. Book of Abstracts, 218th ACS National Meeting, 1999, MEDI-082.
31. T. Mirzadegan, F. Diehl, B. Ebi, S. Bhakta, I. Polsky, D. McCarley, M. Mulkins, G.S. Weatherhead, J.M. Lapierre, J. Dankwardt, D. Morgans Jr., R. Wilhelm, and K. Jarnagin J. Biol. Chem. 275 2000 25562
32. I.T. Forbes, D.G. Cooper, E.K. Dodds, D.M. Hickey, R.J. Ife, M. Meeson, M. Stockley, T.A. Berkhout, J. Gohil, P.H. Groot, and K. Moores Bioorg. Med. Chem. Lett. 10 2000 1803
33. J. Witherington, V. Bordas, D.G. Cooper, I.T. Forbes, A.D. Gribble, R.J. Ife, T. Berkhout, J. Gohil, and P.H. Groot Bioorg. Med. Chem. Lett. 11 2001 2177
34. 125I-labeled MCP-1, were prepared by suitable methods or purchased from commercial vendors (Perkin Elmer, Boston, MA). The binding reactions were performed in 50-250 μL of a binding buffer consisting of 1 M HEPES pH 7.2, and 0.1% BSA (bovine serum albumin), for 30 min at room temperature. The binding reactions were terminated by harvesting the membranes by rapid filtration through glass fiber filters (Perkin Elmer) which was presoaked in 0.3% polyethyleneimine or Phosphate Buffered Saline (PBS). The filters were rinsed with approximately 600 μL of binding buffer containing 0.5 M NaCl or PBS, then dried, and the amount of bound radioactivity was determined by counting on a Gamma Counter (Perkin Elmer).
35. 2 for 30 min. The cells were then aspirated off, the chamber lid opened, and the filter gently removed. The top of the filter was washed three times with PBS and the bottom was left untouched. The filter was air dried and stained with Wright Geimsa stain (Sigma). Filters were counted by microscopy. The negative control wells served as background and were subtracted from all values. Antagonist potency was determined by comparing the number of cells that migrated to the bottom chamber in wells which contained antagonist, to the number of cells which migrated to the bottom chamber in MCP-1 control wells.
36. C.M. Brodmerkel, R. Huber, M. Covington, S. Diamond, L. Hall, R. Collins, L. Leffet, K. Gallagher, P. Feldman, P. Collier, M. Mark Stow, X. Gu, F. Baribaud, N. Shin, B. Thomas, T. Burn, G. Hollis, S. Yeleswaram, K. Solomon, S. Friedman, A. Wang, C.B. Xue, R.C. Newton, P. Scherle, and K. Vaddi J. Immunol. 175 2005 5370
37. + = 237. To a solution of the above crude product in THF (200 mL) was added di-tert-butyldicarbonate (26.8 g, 123 mmol) and triethylamine (17.1 mL, 123 mmol) at 0 °C.
38. N. Shin, F. Baribaud, K. Wand, G. Yang, R. Wynn, M.B. Covington, P. Feldman, K.B. Gallagher, L.M. Leffet, Y.Y. Lo, A. Wang, C.-B. Xue, R.C. Newton, and P.A. Scherle Biochem. Biophys. Res. Commun. 387 2009 251
39. S.P. Weisberg, D. Hunter, R. Huber, J. Lemieux, S. Slaymaker, K. Vaddi, I. Charo, R.L. Leibel, and A.W. Ferrante Jr. J. Clin. Invest. 116 2006 1457