Discovery of 4′-(1,4-dihydro-indeno[1,2- c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2- c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 21; pp. 5944 - 5951
• Main Authors: Tao, Zhi-Fu, Li, Gaoquan, Tong, Yunsong, Stewart, Kent D., Chen, Zehan, Bui, Mai-Ha, Merta, Philip, Park, Chang, Kovar, Peter, Zhang, Haiying, Sham, Hing L., Rosenberg, Saul H., Sowin, Thomas J., Lin, Nan-Horng
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.2007; Elsevier
• Subjects: Antineoplastic agents; Antitumor agent; Biological and medical sciences; Checkpoint Kinase 1; Chk1 inhibitors; Combination therapy; DNA damage; General aspects; Medical sciences; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - drug effects; Pyrazole; Structure-Activity Relationship; Chk1 inhibitors; Checkpoint kinase 1; DNA damage; Antitumor agent; Combination therapy; Pyrazole; Structure–activity relationship; Antineoplastic agent; Nitrile; Nitrogen heterocycle; Non-specific serine/threonine protein kinase; Cytotoxicity; Uterine cervix; Doxorubicin; Synergism; Pyridine derivatives; Signal transduction; Isomerases; Structure activity relation; Structure-activity relationship; Chkl inhibitors; Benzonitrile derivatives; Aromatic compound; Tumor cell; Human; DNA topoisomerase (ATP-hydrolysing); Drug combination; Enzyme; Transferases; Enzyme inhibitor; Tricyclic compound; In vitro; Hela cell line; Cell line; Anthracyclins
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.07.102

An extensive structure–activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4′-(1,4-dihydro-indeno[1,2- c]pyrazol-3-yl)-benzonitriles ( 4) and 4′-(1,4-dihydro-indeno[1,2- c]pyrazol-3-yl)-pyridine-2′-carbonitriles ( 29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure–activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing.