Design and synthesis of 1,5-diarylbenzimidazoles as inhibitors of the VEGF-receptor KDR

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 15, 2003, Pages 2485-2488

  Bilodeau, Mark T ^a   Cunningham, April M ^a   Koester, Timothy J ^a   Ciecko, Patrice A ^a   Coll, Kathleen E ^a   Huckle, William R ^a   Hungate, Randall W ^a   Kendall, Richard L ^a   McFall, Rosemary C ^a   Mao, Xianzhi ^a   Rutledge, Ruth Z ^a   Thomas, Kenneth A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZIMIDAZOLE DERIVATIVE; DYES, REAGENTS, INDICATORS, MARKERS AND BUFFERS; ENZYME INHIBITOR; TYROSINE KINASE RECEPTOR; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR; VASCULOTROPIN RECEPTOR 2;

ANIMAL; ANIMAL EXPERIMENT; ARTICLE; CONFORMATION; CONTROLLED STUDY; DOG; DRUG BINDING; DRUG DESIGN; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HALF LIFE TIME; HUMAN; HUMAN CELL; NONHUMAN; PH; PHYSICAL CHEMISTRY; PROTEIN BINDING; RAT; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

EID: 10744227006     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00485-2     Document Type: Article

References (23)

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17. 1H NMR and mass spectroscopy.
18. 50 value represents biochemical inhibition of phosphorylation of a poly-Glu/Tyr (4:1) peptide substrate by isolated KDR kinase (cloned and expressed as a GST-fusion protein): see, Kendall, R. L.; Rutledge, R. Z.; Mao, X.; Tebben, A. L.; Hungate, R. W.; Thomas, K. A. J. Biol. Chem. 1999, 274, 6453. Values are reported as single determinations or as the average of at least two determinations±standard deviation.
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20. 50 value represents the inhibition of VEGF-stimulated mitogenesis as determined in human umbilical vein endothelial cells. For the key compounds 3, 4 and 7 the averages are based on 3, 34 and 7 determinations respectively.
21. Partition coefficients were determined by adding an aliquot of a methanolic sample solution to equal volumes of 1-octanol and pH 7.4 buffer and measuring the concentration in each after an equilibration period of 8 h. Buffer solubilities were determined by comparing the HPLC peak area of a filtered, saturated solution of compound in pH adjusted buffer to peaks from standard methanolic solutions. Protein binding to human plasma is determined by equilibrating buffer solutions of test compounds and human plasma and using ultrafiltration for separation. The free compound concentration is measured by HPLC.
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23. Compound 4 was prepared according to the synthesis of 3, beginning with 5-bromo-2-chloro-3-nitropyridine. Compounds 5, 8 and 10 were derived from alkyation of 5-iodopyridin-2-ol and subsequent coupling with the boronate ester in Scheme 2. Compound 6 was prepared by coupling of the boronate ester with 5-bromo-2-fluoropyridine and displacement of the resulting fluoride with (2-morpholin-4-ylethyl)amine. Compound 9 was prepared according to the synthesis of 7, using the homologous alkylating reagent. Compound 11 was prepared by coupling of the boronate ester with 4-chloro-2-(methylthio)pyrimidine, followed by hydrolysis of the thiomethyl-functionality and alkylation according to Scheme 2.