E. J. Iwanowicz et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2059–2063
2063
and without the appending methoxy moiety. Thus, the
methoxy group on the phenyl ring was omitted in the
4-methyl oxazole containing analogues 34a–e, and th e 2,4-
dimethyl analogue 36. The methoxy group was retained in
the 2-methyl analogue 35. Withthe exception of 34a, all of
these compounds were significantly less potent than the
corresponding analogues fashioned with MOA.
5. Watterson, S.; Liu, C.; Dhar, T. G. M.; Gu, H. H.; Pitts,
W. J.; Barrish, J. C.; Fleener, C. F.; Rouleau, K.; Sherbina,
N. Z.; Hollenbaugh, D. H.; Iwanowicz, E. J. Bioorg. Med.
Lett. 2002, 12, 2879.
6. Gu, H. H.; Iwanowicz, E. J.; Guo, J.; Watterson, S. H.;
Shen, Z.; Pitts, W. J.; Dhar, T. G. M.; Fleener, C. F.; Rouleau,
K.; Sherbina, N. Z.; Witmer, M.; Tredrup, J.; Hollenbaugh,
D. H. Bioorg. Med. Lett. 2002, 9, 1323.
7. Pitts, W. J.; Guo, J.; Dhar, T. G. M.; Shen, Z.; Gu, H. H.;
Watterson, S. H.; Bednarz, M. S.; Chen, B.-C.; Barrish, J. C.;
Bassolino, D.; Cheney, D.; Fleener, C. A.; Rouleau, K. A.;
Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg. Med. Lett. 2002,
12, 2137.
8. Dhar, T. G. M.; Watterson, S. H.; Liu, C.; Barrish, J. C.;
Fleener, C. A.; Rouleau, K.; Sherbina, N. Z.; Hollenbaugh,
D.; Iwanowicz, E. J. Bioorg. Med. Lett. 2002, 12, 3153.
9. Dhar, T. G. M.; Watterson, S. H.; Liu, C.; Barrish, J. C.;
Fleener, C. A.; Rouleau, K.; Sherbina, N. Z.; Hollenbaugh,
D.; Iwanowicz, E. J. Bioorg. Med. Lett. 2002, 12, 3125.
10. Dhar, T. G. M.; Shen, Z.; Fleener, C. A.; Rouleau, K.;
Barrish, J. C.; Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg.
Med. Lett. 2002, 12, 3305.
11. Watterson, S. H.; Carlsen, M.; Dhar, T. G. M.; Shen, Z.;
Pitts, W. J.; Guo, J.; Gu, H. H.; Norris, D.; Chorba, J.; Chen,
P.; Cheney, D.; Fleener, C. A.; Rouleau, K.; Hollenbaugh, D.
H.; Iwanowicz, E. J., Bioorg. Med. Lett. 2003, 13, 543.
12. Dhar, T. G. M.; Watterson, S. H.; Chen, P.; Shen, Z.; Gu,
H. H.; Norris, D.; Carlsen, M.; Haslow, K. D.; Pitts, W. J.; Guo,
J.; Chorba, J.; Fleener, C. A.; Rouleau, K. A.; Townsend, R.
Hollenbaugh, D.; Iwanowicz, E. J. Bioorg. Med. Lett. 2003, 13,
547.
The oxazole-4-yl analogues of 1e were generally slightly
less potent than their corresponding oxazole-5yl ana-
logues. For example, compare 1e to 37b, 30a to 37e, and
30b to 37f (Table 5). The difference in potency was more
pronounced in other inhibitor series, as oxazol-4-yl
analogues 37g, and 38 were greater than 20-fold less
potent than the corresponding analogues 1f and 2,
respectively. It is interesting to note that the chloro
analogue 37d was significantly less potent when com-
pared to the oxazole-5-yl analogue 29d, which is in
contrast to the results previously discussed for the oxazol-
5-yl ring system. The triazole analogue 40 may enter into
a similar hydrogen bond array upon binding as the oxa-
zole-5-yl analogues however this analogue displays only
moderate inhibitory potency. The level of binding affinity
of 39 was 10-fold less than 1e. Our binding hypothesis
predicts that the oxazol-2-yl ring system would not be
able to effectively hydrogen bond with Gly 326, in con-
trast to the oxazole-4-yl and oxazole-5-yl ring systems.
From an examination of the reported crystallographic
data for MPA and VX-497 bound to IMPDH, it is clear
that key hydrophobic and hydrogen bonding inter-
actions involving the benzofuranone and oxazole phenyl
moieties are critical for the low nM binding affinities
observed for these analogues. Our studies have defined
the sensitivity to chemical modification about the oxa-
zole phenyl moiety and have established that formation
of a hydrogen bond between the inhibitor, Gly 326 and
Thr 333 as important for achieving high potency. Addi-
tional studies of structurally novel inhibitors will further
our understanding of the requirements for achieving
maximal binding affinity for MOA replacements. These
studies will be the subject of future reports.
13. Chen, P.; Norris, D.; Halsow, K. D.; Dhar, T. G. M.;
Pitts, W. J.; Watterson, S. H.; Cheney, D. L.; Fleener, C. A.;
Rouleau, K. A.; Hollenbaugh, D. L.; Barrish, J. C.; Iwano-
wicz, E. J. 2003, 13, 1345.
14. Bjarnason, I. Transplant. Proc. 2001, 33, 3238.
15. Salvadori, M. Transplant. Proc. 2001, 33, 3245.
16. Granger, D. K. Transplant. Proc. 2001, 33, 3241.
17. Sintchak, M. D.; Fleming, M. A.; Futer, O.; Raybuck,
S. A.; Chambers, S. P.; Caron, P. R.; Murcko, M. A.; Wilson,
K. P. Cell 1996, 85, 921.
18. Sintchak, M. D.; Nimmesgern, E. Immunopharmacology
2000, 47, 163.
19. The IMPDH II inhibition assay and the CEM prolifera-
tion protocol are outlined in ref 2.
20. Conversion of the methyoxy group to an ethoxy group
was accomplished at a late stage for 26c as depicted below:
References and Notes
1. Sievers, T. M.; Rossi, S. J.; Ghobrial, R. M.; Arriola, E.;
Nishimura, P.; Kawano, M.; Holt, C. D. Pharmacotherapy
1997, 17, 1178.
2. Jain, J.; Almquist, S. J.; Shlyakhter, D.; Harding, M. W. J.
Pharm. Sci. 2001, 90, 625.
3. Dhar, T. G. M.; Shen, Z.; Guo, J.; Liu, C.; Watterson,
S. H.; Gu, H. H.; Pitts, W. J.; Fleener, C. A.; Rouleau, K. A.;
Sherbina, N. Z.; McIntyre, K. W.; Witmer, M. R.; Tredup,
J. A.; Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Cheney, D. L.;
MacMaster, J. F.; Miller, L. M.; Berry, K. K.; Harper, T. W.;
Barrish, J. C.; Hollenbaugh, D. L.; Iwanowicz, E. J. J. Med.
Chem. 2002, 45, 2127.
Reagents and conditions: (a) (Boc)2O, DMAP, Et3N, DMSO
95%; (b) BBr3, CH2Cl2, 93%; (c) EtI, K2CO3, DMF, reflux, 2 h ,
20%.
4. Iwanowicz, E. J.; Watterson, S. H.; Lui, C.; Gu, H. H.; Mitt, T.;
Leftheris, K.; Barrish, J. C.; Fleener, C. A.; Rouleau, K.; Sherbina,
N. Z.; Hollenbaugh, D. Bioorg. Med. Lett. 2002, 12, 2931.