Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors.

The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).

[1]  Daniel F Ortwine,et al.  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution. , 2006, Journal of medicinal chemistry.

[2]  P. Furet,et al.  Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. , 1999, Pharmacology & therapeutics.

[3]  Michael Reilly,et al.  Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[4]  Jiri Bartek,et al.  Targeting the checkpoint kinases: chemosensitization versus chemoprotection , 2004, Nature Reviews Cancer.

[5]  D. E. Clark.  Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. , 1999, Journal of pharmaceutical sciences.

[6]  Z. Tao,et al.  Chk1 inhibitors for novel cancer treatment. , 2006, Anti-cancer agents in medicinal chemistry.

[7]  M. Yin,et al.  Targeting Molecular Signals in Chk1 Pathways as a New Approach for Overcoming Drug Resistance , 2004, Cancer and Metastasis Reviews.

[8]  Maurizio Recanatini,et al.  Safety of Non-Antiarrhythmic Drugs that Prolong the QT Interval or Induce Torsade de Pointes , 2002, Drug safety.

[9]  Z. Rankovic,et al.  Medicinal chemistry of hERG optimizations: Highlights and hang-ups. , 2006, Journal of medicinal chemistry.

[10]  G Camenisch,et al.  Cell permeability as a parameter for lead generation in the protein Tyrosine kinase inhibition field. , 2001, Bioorganic & medicinal chemistry letters.

[11]  R. Sridhar,et al.  An efficient synthesis of 1-H-pyrazole-4-carboxylic acid esters with vilsmeier reagent under neat conditions , 2004 .

[12]  A. Kral,et al.  Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors , 2022 .

[13]  Kinesin spindle protein (KSP) inhibitors. Part 2: the design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP. , 2006, Bioorganic & medicinal chemistry letters.

[14]  M. Soufiaoui,et al.  Nouvelle voie de synthese d'arylpyrazolo -[4,3-c]-quinoleines via la cycloaddition dipolaire −1,3 , 1989 .

[15]  T. Kawabe.  G2 checkpoint abrogators as anticancer drugs. , 2004, Molecular cancer therapeutics.

[16]  M. Prudhomme.  Novel checkpoint 1 inhibitors. , 2006, Recent patents on anti-cancer drug discovery.

[17]  B. Pfeiffer,et al.  Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors. , 2007, European journal of pharmacology.

[18]  Jiri Bartek,et al.  Chk1 and Chk2 kinases in checkpoint control and cancer. , 2003, Cancer cell.