Referenced in: none

Automatically associated channels: Kv11.1

Title: 1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

Authors: Jürgen Dinges, Daniel H Albert, Lee D Arnold, Kimba L Ashworth, Irini Akritopoulou-Zanze, Peter F Bousquet, Jennifer J Bouska, George A Cunha, Steven K Davidsen, Gilbert J Diaz, Stevan W Djuric, Alan F Gasiecki, Gary A Gintant, Vijaya J Gracias, Christopher M Harris, Kathryn A Houseman, Charles W Hutchins, Eric F Johnson, Hu Li, Patrick A Marcotte, Ruth L Martin, Michael R Michaelides, Michelle Nyein, Thomas J Sowin, Zhi Su, Paul H Tapang, Zhiren Xia, Henry Q Zhang

Journal, date & volume: J. Med. Chem., 2007 May 3 , 50, 2011-29

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17425296

Abstract
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.