4392
G. D. Cuny et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4388–4392
11. (a) Also know in the literature as ‘‘compound C”.; This compound was initially
Acknowledgments
reported as an AMP-activated protein kinase (AMPK) inhibitor, see: (b) Zhou,
G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.;
Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M. F.; Goodyear, L. J.; Moller, D. E. J.
Clin. Invest. 2001, 108, 1167.
The authors thank Partners Healthcare for financial support. This
work was also supported in part by NIH Grants HL079943 (P.B.Y.),
HL074352 (K.D.B.), and HL079267 (R.T.P.), the Harvard NeuroDis-
covery Center (G.D.C., X.X. and J.K.L.), a Pulmonary Hypertension
Association Mentored Clinical Scientist Award (P.B.Y.) and a grant
from the GlaxoSmithKline Research & Education Foundation for Car-
diovascular Disease (P.B.Y.). The pharmacokinetic study was per-
formed by Absorption Systems (Exton, PA) and the microsome
stability experiments were performed by Cyprotex (Macclesfield,
UK).
12. For similar compounds reported as KDR kinase inhibitors see: (a) Fraley,
M. E.; Hoffman, W. F.; Rubino, R. S.; Hungate, R. W.; Tebben, A. J.;
Rutledge, R. Z.; McFall, R. C.; Huckle, W. R.; Kendall, R. L.; Coll, K. E.;
Thomas, K. A. Bioorg. Med. Chem. Lett. 2002, 12, 2767; (b) Fraley, M. E.;
Rubino, R. S.; Hoffman, W. F.; Hambaugh, S. R.; Arrington, K. L.; Hungate,
R. W.; Bilodeau, M. T.; Tebben, A. J.; Rutledge, R. Z.; Kendall, R. L.; McFall,
R. C.; Huckle, W. R.; Coll, K. E.; Thomas, K. A. Bioorg. Med. Chem. Lett.
2002, 12, 3537.
13. Daniels, R. N.; Kim, K.; Lebois, E. P.; Muchalski, H.; Hughes, M.; Lindsley, C. W.
Tetrahedron Lett. 2008, 49, 305.
14. 13: 1H NMR (DMSO-d6)d 9.75 (d, J = 2.2 Hz, 1H), 9.40 (br s, 1H), 9.29 (d, J = 5.9 Hz,
1H), 9.28 (d, J = 2.2 Hz, 1H), 9.07 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 5.9 Hz,
1H), 8.47 (d, J = 8.4 Hz, 1H), 8.21 (t, J = 7.6 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.88 (d,
J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 3.51–3.58 (m, 4H), 3.20–3.30 (m, 4H);
HRMS m/z 407.1979 (calcd for C25H23N6, MH+, 407.1979).
Supplementary data
15. (a) Prepared from quinoline-4-carboxaldehyde in three steps: (i) reduction
(NaBH4, MeOH, 0 °C to rt); (ii) conversion of the alcohol to a chloride (2 equiv
SOCl2, DCM, 0 °C to rt); (iii) conversion of the chloride to a nitrile (NaCN, DMF,
rt).; For an alternate procedure see: (b) Engler, T. A.; Furness, K.; Malhotra, S.;
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