2-Aryl benzimidazoles featuring alkyl-linked pendant alcohols and amines as inhibitors of checkpoint kinase Chk2

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 23, 2007, Pages 6467-6471

  Neff, Danielle K ^a   Lee Dutra, Alice ^a   Blevitt, Jonathan M ^a   Axe, Frank U ^a   Hack, Michael D ^a   Buma, Johnathan C ^a   Rynberg, Raymond ^a   Brunmark, Anders ^a   Karlsson, Lars ^a   Breitenbucher, J Guy ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Aminoalcohol; Cds1; Chk2; Mitsunobu; Solubility

Indexed keywords

2 BENZIMIDAZOLE DERIVATIVE; BENZIMIDAZOLE; CHECKPOINT KINASE 2; UNCLASSIFIED DRUG;

ARTICLE; ATAXIA TELANGIECTASIA; DRUG ACTIVITY; DRUG MECHANISM; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HYDROGEN BOND; STRUCTURE ACTIVITY RELATION;

ALCOHOLS; AMINES; BENZIMIDAZOLES; HYDROGEN BONDING; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES;

EID: 35648956768     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.09.098     Document Type: Article

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10. Equilibrium solubility: Solubility samples were prepared by mixing 400 μmol of compounds (solids dissolved in DMSO) with either 1 mL of SGF (0.1 N HCl, 0.2% NaCl, pH 1.2) or FasSIF (Galia et al. Pharm. Res. 15(5), 698-705, 1998) for at least 3 days at room temperature. The resulting mixtures were then filtered and the supernatants were analyzed by UV-HPLC against external standards.
11. 2, 25 μM synthetic peptide substrate (Biotin-SGLYRSPSMPENLNRPR, 1 μM ATP, 50 μCi/mL [g-33P]) ATP, and a protease inhibitor mixture. The reaction mixtures were incubated at 37 °C for 3 h, and the peptide substrate was captured on streptavidin conjugated to agarose beads. The agarose beads were washed repeatedly with a 0.1% solution of Tween-20 in phosphate-buffered saline, pH 7.4. Enzyme activity at different Chk2 inhibitory compound concentrations was determined by measuring the amount of radioactive phosphate bound to the substrate peptide by scintillation counting.