Discovery of novel 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones as potent and selective inhibitors of KDR: Synthesis, SAR, and pharmacokinetic properties

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 14, 2008, Pages 4054-4058

  Choquette, Deborah ^a   Teffera, Yohannes ^a   Polverino, Anthony ^a   Harmange, Jean Christophe ^a  

^a AMGEN INC   (United States)

Author keywords

1,2,3,4 Trahydroisoquinolines; 3,4 Dihydroisoquinoline 1(2H) ones; KDR; VEGFR 2

Indexed keywords

3,4 DIHYDROISOQUINOLINE 1(2H) ONE DERIVATIVE; TETRAHYDROISOQUINOLINE; VASCULOTROPIN RECEPTOR 2;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DISTRIBUTION VOLUME; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROPHOBICITY; IC 50; IN VITRO STUDY; LIPOPHILICITY; MALE; NONHUMAN; RAT; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; ENDOTHELIUM, VASCULAR; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; ISOQUINOLINES; MALE; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROISOQUINOLINES; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 47149099511     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.05.114     Document Type: Article

References (16)

1. Folkman J. Ann. Surg. 175 (1972) 409
2. Ferrara N. Nat. Rev. Cancer 2 (2002) 795
3. Hurwitz H., Fehrenbacher L., Novotny W., Cartwright T., Hainsworth J., Heim W., Berlin J., Baron A., Griffing S., Holmgren E., Ferrara N., Fyfe G., Rogers B., Ross R., and Kabbinavar F. N. Engl. J. Med. 350 (2004) 2335
4. Burris III H.A., Hurwitz H.I., Dees E.C., Dowlati A., Blackwell K.L., O'Neil B., Marcom P.K., Ellis M.J., Overmoyer B., Jones S.F., Harris J.L., Smith D.A., Koch K.M., Stead A., Mangum S., and Spector N.L. J. Clin. Oncol. 23 (2005) 5305
5. Mross K., Drevs J., Muller M., Medinger M., Marme D., Hennig J., Morgan B., Lebwohl D., Masson E., Ho Y.Y., Gunther C., Laurent D., and Unger C. Eur. J. Cancer 41 (2005) 1291
6. Thomas A.L., Morgan B., Horsfield M.A., Higginson A., Kay A., Lee L., Masson E., Puccio-Pick M., Laurent D., and Steward W.P. J. Clin. Oncol. 23 (2005) 4162
7. Harmange J.-C., Weiss M., Germain J., Polverino A., Borg G., Bready J., Chen D., Choquette D., Coxon A., DeMelfi T., DiPietro L., Doerr N., Estrada J., Flynn J., Graceffa R., Harriman S., Kaufman S., La D., Long A., Martin M., Neervannan S., Patel V., Potashman M., Regal K., Roveto P., Schrag M., Starnes C., Tasker A., Teffera Y., Wang L., White R., Whittington D., and Zanon R. J. Med. Chem. 51 (2008) 1649
8. 4, and 0.22 M KCl.
9. See Supplemental material for experimental details regarding the preparation of 4-chloromethyl-6,7-dimethoxyquinoline 15.
10. See Supplemental material for experimental details regarding the regioselective oxidation of 6 and 7.
11. Cellular potency was evaluated by determining the inhibition of human umbilical vein endothelial cell (HUVEC) proliferation induced by vascular endothelial growth factor (VEGF). In addition, the HUVEC proliferation assay was used to assess selectivity at the cellular level comparing on-target inhibition of VEGF driven proliferation and off-target fibroblast growth factor (FGF) driven proliferation. Although both growth factors, VEGF and FGF, induce HUVEC proliferation, each operates through a different signaling pathway. For a detailed description of the KDR enzyme and cellular assays, see Ref. 3.
12. La D., Belzile J., Bready J.V., Coxon A., DeMelfi T., Doerr N., Estrada J., Flynn J.C., Flynn S.R., Graceffa R.F., Harriman S.P., Larrow J.F., Long A.M., Martin M., Morrison M.J., Patel V., Roveto P.M., Wang L., Weiss M.M., Whittington D.A., Teffera Y., Zhao Z., Polverino A.J., and Harmange J.-C. J. Med. Chem. 51 (2008) 1695
13. Weiss M.M., Harmange J.-C., Polverino A.J., Bauer D., Berry L., Berry V., Borg G., Bready J., Chen D., Choquette D., Coxon A., DeMelfi T., Doerr N., Estrada J., Flynn J., Graceffa R.F., Harriman S.P., Kaufman S., La D., Long A., Neervannan S., Patel V., Potashman M., Regal K., Roveto P., Schrag M., Starnes C., Tasker A., Teffera Y., Whittington D., and Zanon R. J. Med. Chem. 51 (2008) 1668
14. Intrinsic clearance values were determined using 0.25 mg microsomal protein/mL, 1 mM NADPH, and 1 μM test compound in 50 mM potassium phosphate buffer. Samples were collected at 0, 10, 20, 30, and 40 min. Intrinsic clearance was determined from the half-life.
15. Liver microsomal (HLM, RLM) incubations were conducted using 1 mg/mL protein, 10 μM of test compound at 37 °C for 60 min, with or without NADPH (1 mM).
16. Compound 27 exhibits >100× selectivity against the following kinases: Aurora 1, Aurora 2, BTK, c-Met, JAK3, and PI3Kδ. In addition, compound 27 demonstrates >10× selectivity against c-FMS, TIE2, and LCK.