Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 4, Pages 1429-1440Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.12.055
Keywords
Hedgehog signaling pathway; Inhibitors; Pyrrolo[2,1-f][1,2,4]triazine; Novel
Funding
- National Major Science and Technology Project of China [2011ZX09401-008]
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A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo. (C) 2014 Elsevier Ltd. All rights reserved.
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