1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies |
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| Authors: | Tong Yunsong Claiborne Akiyo Pyzytulinska Magdalena Tao Zhi-Fu Stewart Kent D Kovar Peter Chen Zehan Credo Robert B Guan Ran Merta Philip J Zhang Haiying Bouska Jennifer Everitt Elizabeth A Murry Bernard P Hickman Dean Stratton Tim J Wu Jian Rosenberg Saul H Sham Hing L Sowin Thomas J Lin Nan-horng |
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| Affiliation: | Cancer Research, Global Pharmaceutical R&D, R47S, AP10, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com |
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| Abstract: | A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC(50) values below 0.3nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed. |
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