Elrick, M. M.; Funckes-Shippy, C. L.; Warner, J. D.; Gross, C. J.;
Dowty, M. E.; Ramaiah, S. K.; Hirsch, J. L.; Saabye, M. J.; Barks,
J. L.; Kishore, N.; Morris, D. L. J. Inflamm. 2010, 7, 41. (b) Hoock
T.; Hogan J.; Mahajan S.; Shlyakhter, D.; Oh, L.; Park, L.; Ku, G.
Arthritis Rheum. 2011; 63(Suppl 10), 1136.
synthesis of intermediate 10, Peng Li and Dauh-Rurng Wu for
separating enantiomers 5g and 5h, Marta Dabros for X-ray
crystallography study of 5h, Georgia Cornelius for analyzing
PK samples of 5g and our colleagues in the Lead Evaluation
group for their assistance during this SAR study.
14. (a) Borzilleri, R. M.; Chen, Z.; Hunt, J. T.; Huynh, T.; Poss, M. A.;
Schroeder, G. M.; Vaccaro, W.; Wong, T. W.; Chen, X.-T.; Kim, K.
S. U.S. Pat. Appl. US 20060004006, 2006. (b) Ruxer, J. M.;
Lachoux, C.; Ousset, J. B.; Torregrosa, J. L.; Mattioda, G. J.
Heterocycl. Chem. 1994, 31, 409.
References and Notes
1. For a recent review of immunomodulatory roles of JAKs, see:
O’Shea, J. J.; Plenge, R. Immunity 2012, 36, 542.
15. For preparation of amine intermediates towards the synthesis of 4i
and 4j, see: (a) Yang, Z.; Zhou, Z.; Tang, C. Syn. Commun. 2001,
31, 3031. (b) Yang, Z. H.; Wang, L. X.; Zhou, Z. H.; Zhou, Q. L.;
Tang, C. C. Tetrahedron: Asymmetry 2001, 12, 1579.
2. For a recent review of JAK inhibitors for inflammatory diseases,
see: Clark, J. D.; Flanagan, M. E.; Telliez, J.-B. J. Med. Chem.
2014, 57, 5023.
3. Flanagan, M. E.; Blumenkopf, T. A.; Brissette, W. H.; Brown, M.
F.; Casavant, J. M.; Shang-Poa, C.; Doty, J. L.; Elliott, E. A.;
Fisher, M. B.; Hines, M.; Kent, C.; Kudlacz, E. M.; Lillie, B. M.;
Magnuson, K. S.; McCurdy, S. P.; Munchhof, M. J.; Perry, B. D.;
Sawyer, P. S.; Strelevitz, T. J.; Subramanyam, C.; Sun, J.; Whipple,
D. A.; Changelian, P. S. J. Med. Chem. 2010, 53, 8468.
16. Single crystal X-ray crystallography on compound 5h established
the (1S,2R) configuration for 5h and, through process of
elimination, the (1R,2S) configuration for compound 5g.
4. (a) Cutolo, M.; Meroni, M. J. Inflamm. Res. 2013, 6, 129. (b) Lee,
E. B.; Fleischmann, R.; Hall, S.; Wilkinson, B.; Bradley, J. D.;
Gruben, D.; Koncz, T.; Krishnaswami, S.; Wallenstein, G. V.;
Zang, C.; Zwillich, S. H.; Vollenhoven, R. F. N. Eng. J. Med. 2014,
370, 2377.
5. Menter, A.; Papp, K. A.; Tan, H.; Tyring, S.; Wolk, R.; Buonanno,
M. J. Drugs Dermatol. 2014, 13, 252.
6. Rokosz, L. L.; Beasley, J. R.; Carroll, C. D.; Lin, T.; Zhao, J.;
Appell, K. C.; Webb, M. L. Expert. Opin. Ther. Targets 2008, 12,
883.
7. For a review of JAK3 inhibitors, see: Wrobleski, S. T.; Pitts, W. J.
Annu. Rep. Med. Chem. 2009, 44, 247.
8. For importance of JAK1 in JAK3/JAK1 signaling pathway, see:
Haan, C.; Rolvering, C.; Raulf, F.; Kapp, M.; Drueckes, P.; Thoma,
G.; Behrmann, I.; Zerwes, H.-G. Chem. Biol. 2011, 18, 314.
9. For a structurally related system derived from 1H-pyrrolo[2,3-
b]pyridines, see: Inoue, T.; Tanaka, A.; Nakai, K.; Sasaki, H.;
Takahashi, F.; Shirakami, S.; Hatanaka, K.; Nakajima, Y.;
Mukoyoshi, K.; Hamaguchi, H.; Kunikawa, S.; Higashi, Y. PCT
Appl. WO 2007077949, 2007.
10. Chrencik, J. E.; Patny, A.; Leung, I. K.; Korniski, B.; Emmons, T.
L.; Hall, T.; Weinberg, R. A.; Gormley, J. A.; Williams, J. M.; Day,
J. E.; Hirsch, J. L.; Kiefer, J. R.; Leone, J. W.; Fischer, H. D.;
Sommers, C. D.; Huang, H.-C.; Jacobsen, E. J.; Tenbrink, R. E.;
Tomasselli, A. G.; Benson, T. E. J. Mol. Biol. 2010, 400, 413.
11. IC50 values for JAK3 enzyme inhibition were measured using a
filter assay. IC50 values for JAK1, JAK2 and TYK2 enzyme
inhibition were measured using Caliper assays. An IL2-induced
STAT3 phosphorylation in PHA blast cells was used to assess the
effects of JAK inhibitors on JAK3-JAK1 pathway. An EPO-
induced STAT5A phosphorylation in TF-1 cells was used to assess
the effects of JAK inhibitors on JAK2 pathway. For description of
these assays, see: Wrobleski, S. T.; Brown, G. D.; Doweyko, L.
M.; Duan, J.; Guo, J.; Hynes, J.; Jiang, B., Kempson, J.; Lin, S.; Lu,
Z.; Spergel, S. H.; Tokarski, J. S.; Wu, H.; Yang, B. V. PCT Appl.
WO2012125886, 2012.
12. The whole blood assay was carried out in 96-well flat bottom tissue
culture plates. Human whole blood was stimulated, in the presence
or absence of test compounds, with 1 μg/ml soluble anti-CD3
(R&D Systems), 10 ng/ml anti-CD28 (R&D Systems) and 10 ng/ml
IL-2 (BD Biosciences). The final volume of the assay was 200 μl
with 50% whole blood in RPMI 1640 (Gibco). The cells were
incubated at 37°C in 5% CO2 in a humidified incubator for 18
hours. The plates were centrifuged and supernatant was removed.
IFN-γ levels in the supernatant were determined using a human
IFN-γ ELISA set (BD Biosciences). Compounds were dissolved at
10 mM in dimethylsufoxide (DMSO) and tested at 6 concentrations
in triplicate. IC50 values were derived by non-linear regression
analysis.
13. For precedence of JAK inhibitors with higher functional than
enzyme selectivity, see: (a) Meyer, D. M.; Jesson, M. I.; Li, X.;