Y. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1527–1531
1531
Table 6
Paradis, T. J.; Ogborne, K. T.; Loetscher, M.; Gladue, R. P.; Lin, W.; Boyd, J. G.;
Moser, B.; Wood, D. E.; Sahagan, B. G.; Neote, K. J. Exp. Med. 1998, 187, 2009; (c)
Turner, J. E.; Steinmetz, O. M.; Stahl, R. A.; Panzer, U. Mini-Rev. Med. Chem. 2007,
7, 1089.
PK profile of lead CXCR3 antagonists
Compds Mouse CXCR3 binding
IC50 (nM)
Rat CXCR3 binding
IC50 (nM)
Rat AUCa
(nM h)
3. (a) Szczucin´ ski, A.; Losy, J. Acta Neurol. Scand. 2007, 115, 137; (b) Sindern, E.;
Patzhold, T.; Ossege, L. M.; Gisevius, A.; Malin, J.-P. J. Neuroimmunol. 2002, 131,
186.
4. Patel, D. D.; Zachariah, J. P.; Whichard, L. P. Clin. Immunol. 2001, 98, 39.
5. (a) Rosenblum, J. M.; Zhang, Q.-W.; Siu, G.; Collins, T. L.; Sullivan, T.; Dairaghi,
D. J.; Medina, J. C.; Fairchild, R. L. Transplantation 2009, 87, 360; (b) Bastani, S.;
Sherman, W.; Schnickel, G. T.; Hsieh, G. R.; Bhatia, R.; Fishbein, M. C.; Ardehali,
A. Transplantation 2009, 88, 995.
7a
7b
18i
18j
84
97
920
500
410
950
6.7
0.5
1.1
9.9
1.2
1.6
a
PO, 10 mpk, 6 h, 0.4% MC.
6. (a) Rottman, J. B.; Smith, T. L.; Ganley, K. G.; Kikuchi, T.; Krueger, J. G. Lab. Invest.
2001, 81, 335; (b) Homey, B. Curr. Drug Targets Inflamm. Allergy 2004, 3, 169.
7. Pradelli, E.; Karimdjee-Soilihi, B.; Michiels, J.-F.; Ricci, J.-E.; Millet, M.-A.;
Vandenbos, F.; Sullivan, T. J.; Collins, T. L.; Johnson, M. G.; Medina, J. C.;
Kleinerman, E. S.; Schmid-Alliana, A.; Schmid-Antomarchi, H. Int. J. Cancer
2009, 125, 2586.
MC).17 The smaller, more active analogs 18i and 18j maintained
comparable exposure levels (AUC = 410 nM h and 950 nM h,
respectively). Hence, truncation of the R1 carboxamide substituent
was not sufficient to enhance the rat PK profile of this series of
CXCR3 antagonists.
8. Wijtmans, M.; Verzijl, D.; Leurs, R.; de Esch, I. J. P.; Smit, M. J. ChemMedChem
2008, 3, 861.
In summary, modifications were made throughout the piperaz-
inyl-piperidine core of the CXCR3 antagonist 1. While tolerated,
most of the pyridyl carboxamide or benzyl substitutions did not
enhance binding affinity toward the CXCR3 receptor. In contrast,
changes to the 20-position of the piperazine had a strong influence
on receptor binding. A modest increase in the size of the alkyl
group at the 20-position of the piperazine ring from methyl to ethyl,
improved binding affinity significantly, resulting in the first re-
ported sub-nanomolar (IC50) CXCR3 receptor antagonists. Hence,
the 20-position of the piperazine ring is an important pharmaco-
phore element in the interaction of the current lead molecules
18i and 18j with the CXCR3 receptor. Further optimization efforts
in this series will be reported in separate publications.
9. Du, X.; Gustin, D. J.; Chen, X.; Duquette, J.; McGee, L. R.; Wang, Z.; Ebsworth, K.;
Henne, K.; Lemon, B.; Ma, J.; Miao, S.; Sabalan, E.; Sullivan, T. J.; Tonn, G.;
Collins, T. L.; Medina, J. C. Bioorg. Med. Chem. Lett. 2009, 19, 5200.
10. Thoma, G.; Baenteli, R.; Lewis, I.; Wagner, T.; Oberer, L.; Blum, W.; Glickman, F.;
Streiff, M. B.; Zerwes, H.-G. Bioorg. Med. Chem. Lett. 2009, 19, 6185.
11. Wang, Y.; Busch-Petersen, J.; Wang, F.; Kiesow, T. J.; Graybill, T. L.; Jin, J.; Yang,
Z.; Foley, J. J.; Hunsberger, G. E.; Schmidt, D. B.; Sarau, H. M.; Capper-Spudich, E.
A.; Wu, Z.; Fisher, L. S.; McQueney, M. S.; Rivero, R. A.; Widdowson, K. L. Bioorg.
Med. Chem. Lett. 2009, 19, 114.
12. McGuinness, B. F.; Carroll, C. D.; Zawacki, L. G.; Dong, G.; Yang, C.; Hobbs, D.
W.; Jacob-Samuel, B.; Hall, J. W.; Jenh, C.-H.; Kozlowski, J. A.; Anilkumar, G. N.;
Rosenblum, S. B. Bioorg. Med. Chem. Lett. 2009, 19, 5205.
13. (a) Falorin, M.; Giacomelli, G.; Satta, M.; Cossu, S. Synthesis 1994, 4, 391; (b)
Richards, S.; Sorensena, B.; Jaea, H.; Winna, M.; Chena, Y.; Wang, J.; Funga, S.;
Monzona, K.; Freverta, E.; Jacobsona, P.; Shama, H.; Linka, J. T. Bioorg. Med.
Chem. Lett. 2006, 16, 6241.
14. Tagat, J. R.; Steensma, R. W.; McCombie, S. W.; Nazareno, D. V.; Lin, S.;
Neustadt, B. R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M. G.; Vantuno, N.; Baroudy,
B. M.; Strizki, J. M. J. Med. Chem. 2001, 44, 3343.
References and notes
15. Analogs 17e–17i were synthesized as previously described.12
16. Representative compounds 6k, 6l, 7b, 17h and 17i showed functional
anatagonism in CXCR3 mediated chemotaxis assays. For example compound
7b showed IC50 of 23 nM in IP-10 induced hCXCR3 chemotaxis.
17. Sprague–Dawly rat PK of compound 7b was determined: AUC (PO, 5 mpk,
24 h) = 1100 nM h, T1/2 = 6.8 h, Vd[ss] = 17.6 L/kg, and CL = 32.6 mL/min/kg.
1. (a) Lacotte, S.; Brun, S.; Muller, S.; Dumortier, H. Ann. N. Y. Acad. Sci. 2009, 1173,
310; (b) Kelso, A. Immunol. Cell Biol. 1998, 76, 300; (c) Baggiolini, M. Nature
1998, 392, 565; (d) Qin, S.; Rottman, J. B.; Myers, P.; Kassam, N.; Wienblatt, M.;
Loetscher, M.; Koch, A. E.; Moser, B.; Mackay, C. R. J. Clin. Invest. 1998, 101, 746.
2. (a) Loetscher, M.; Gerber, B.; Loetscher, P.; Jones, S. A.; Piali, L.; Clark-Lewis, I.;
Baggiolini, M.; Moser, B. J. Exp. Med. 1996, 184, 963; (b) Cole, K. E.; Strick, C. A.;
Additionally, CYP 2D6, 3A4 and 2C19 inhibition (IC50) was >10 lM.