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Xin M.,Xian Jiaotong University | Xin M.,Jiangsu Simcere Pharmaceutical Co. | Zhang L.,Jiangsu Simcere Pharmaceutical Co. | Tang F.,Jiangsu Simcere Pharmaceutical Co. | And 10 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

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. © 2014 Elsevier Ltd. All rights reserved. Source


Xin M.,Xian Jiaotong University | Xin M.,Jiangsu Simcere Pharmaceutical Co. | Zhang L.,Jiangsu Simcere Pharmaceutical Co. | Shen H.,Jiangsu Simcere Pharmaceutical Co. | And 9 more authors.
Medicinal Chemistry Research | Year: 2014

A novel series of hedgehog signaling pathway inhibitors were designed by replacing the pyrimidine nucleus of our earlier reported compounds with 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine scaffold. Among this new class of hedgehog signaling pathway inhibitors, compounds 14 and 18 exhibited promising potency in vitro compared to GDC-0449. Compound 18 was advanced to profile its pharmacokinetic characteristics, and showed moderate pharmacokinetic properties in vivo, indicating that the 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine skeleton is a promising scaffold for further exploration as hedgehog signaling pathway inhibitors. © Springer Science+Business Media 2014. Source

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