Investigation of a novel molecular descriptor for the lead optimization of 4-aminoquinazolines as vascular endothelial growth factor receptor-2 inhibitors: Application for quantitative structure-activity relationship analysis in lead optimization

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 5, 2011, Pages 1371-1375

  Kawakami, Joel K ^a   Martinez, Yannica ^a   Sasaki, Brandi ^a   Harris, Melissa ^a   Kurata, Wendy E ^b   Lau, Alan F ^b  

^a CHAMINADE UNIVERSITY OF HONOLULU   (United States)

^b UNIVERSITY OF HAWAII CANCER CENTER   (United States)

Author keywords

4 Anilinoquinazoline; Infrared; KDR; Molecular descriptor; VEGFR 2

Indexed keywords

3' CHLORO 4' METHYL ANILINO; 3' FLUORO 4' METHYL ANILINO; 3',4' DIFLUORO ANILINO; 4 AMINOQUINAZOLINE; 4' CHLORO ANILINO; 4' FLUORO ANILINO; ANILINO; CYCLOHEXYLAMINE; ETHOXYL; ISOPROPOXYL; ISOPROPYL AMINE; PYRAZOLO[1,5-A]PYRIMIDINE; UNCLASSIFIED DRUG; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR 2;

ARTICLE; DRUG BINDING; DRUG SYNTHESIS; INFRARED RADIATION; INFRARED VIBRATIONAL FREQUENCY; MOLECULAR DOCKING; MOLECULAR WEIGHT; QUANTITATIVE STRUCTURE ACTIVITY RELATION; X RAY DIFFRACTION;

AMINES; DRUG DESIGN; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; QUINAZOLINES; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 79951722444     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.037     Document Type: Article

References (26)

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14. Calculation of MDIR for compound 2 as a representative example: Compound 2 Qty IR Sub total Functional group -C-H 23 1480 34,040 C-C- 8 1680 13,440 -CC- 4 1680 6720 -CN- 0 1810 0 N-H 0 1600 0 -CN- 0 1810 0 C-H 3 1000 3000 -C-C- 9 1680 15,120 C-O-alcohol 1 1150 1150 -O-H 1 3600 3600 -CO 0 1820 0 -N-H 0 1600 0 -C-O-ether 2 1300 2600 -C-N-alkyl 0 1360 0 c-Cl 0 800 0 C-F 0 1400 0 -CN 0 2260 0 C-N- 0 1360 0 -C-Br 1 600 600 Sum of IR absorptions 80,270 Molecular weight 379.33 MDIR 211.6099
15. 6): δ 11.4 (1H, br s), 8.83 (1H, s), 8.33 (1H, s), 7.77 (2H, br d, J = 9.3 Hz), 7.55 (2H, br d, J = 9.0 Hz), 7.35 (1H, s), 4.02 (3H, s), 4.00 (3H, s).
16. 6): δ 11.3 (1H, br s), 8.85 (1H, s), 8.25 (1H, s), 7.96-7.89 (1H, m), 7.60-7.55 (2H, m), 7.32 (1H, s), 4.01 (3H, s), 4.00 (3H, s).
17. 6): δ 11.3 (1H, br s), 8.85 (1H, s), 8.28 (1H, s), 7.86 (1H, d, J = 1.8 Hz), 7.61 (1H, dd, J = 8.1, 2.4 Hz), 7.46 (1H, d, J = 8.7 Hz), 7.33 (1H, s), 4.02 (3H, s), 4.00 (3H, s), 2.37 (3H, s).
18. 6): δ 11.3 (1H, br s), 8.80 (1H, s), 8.27 (1H, s), 7.71 (2H, br dd, J = 9.3, 5.4 Hz), 7.34 (2H, br t, J = 8.7 Hz), 7.33 (1H, s), 4.01 (3H, s), 4.00 (3H, s).
19. 6): δ 11.4 (1H, s), 8.85 (1H, s), 8.32 (1H, s), 7.64 (1H, dd, J = 11.4, 2.1 Hz), 7.47 (1H, dd, J = 8.4, 1.8 Hz), 7.38 (1H, t, J = 8.7 Hz), 7.34 (1H, s), 4.02 (3H, s), 3.99 (3H, s), 2.27 (3H, d, J = 1.8 Hz).
20. 6): δ 11.4 (1H, br s), 8.80 (1H, s), 8.34 (1H, br d, J = 3.9 Hz), 7.69 (2H, br d, J = 7.2 Hz), 7.50 (1H, br d, J = 7.8 Hz), 7.48 (1H, br d, J = 8.4 Hz), 7.36 (1H, br d, J = 4.8 Hz), 7.32 (1H, br t, J = 7.8 Hz), 4.02 (3H, s), 3.99 (3H, s).
21. 3) δ 8.85 (1H, s), 7.97 (1H, s), 7.41 (1H, s), 4.83 (2H, q, J = 6.9 Hz), 4.14 (3H, s), 4.07 (3H, s), 1.59 (3H, t, J = 6.9 Hz).
22. 3) δ 7.98 (1H, s), 7.62 (1H, s), 7.16 (1H, s), 4.07 (1H, heptet, J = 6.9 Hz), 4.02 (3H, s), 4.02 (3H, s), 1.22 (7H, d, J = 6.9 Hz).
23. 3) δ 8.88 (1H, s), 8.16 (1H, s), 7.44 (1H, s), 4.76 (1H, heptet, J = 6.9 Hz), 4.17 (3H, s), 4.08 (3H, s), 1.47 (6H, d, J = 6.9 Hz).
24. 3) δ 8.39 (1H, s), 7.44 (1H, s), 7.28 (1H, s), 4.32-4.28 (1H, m), 4.11 (3H, s), 3.98 (3H, s), 3.14 (1H, tt, J = 11.0, 3.9 Hz), 2.14-2.10 (2H, m), 1.85-1.81 (2H, m), 1.63-1.25 (5H, m).
25. i 8751 were both purchased from Tocris Bioscience and used as received.
26. 3): δ 8.79 (1H, d, J = 2.4 Hz), 8.77 (1H, d, J = 2.4 Hz), 8.37 (1H, s), 7.90 (1H, dd, J = 3.0, 1.2 Hz), 7.70 (1H, dd, J = 5.1, 1.2 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.43 (1H, dd, J = 5.1, 3.0 Hz), 7.06 (2H, d, J = 8.7 Hz), 3.89 (s, 3H).