Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors

Bioorg Med Chem. 2014 Feb 15;22(4):1429-40. doi: 10.1016/j.bmc.2013.12.055.

Minhang Xin ¹, Liandi Zhang ², Feng Tang ³, Chongxing Tu ³, Jun Wen ², Xinge Zhao ³, Zhaoyu Liu ², Lingfei Cheng ³, Han Shen ²

Affiliations

1 Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China. Electronic address: xmhcpu@163.com.
2 Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
3 Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China; Nanjing BioSciKin Co. Ltd, Small Molecule Drug Discovery Platform, No 699-18, Xuan Wu District, Nanjing 210042, PR China.

PMID: 24486203 DOI: 10.1016/j.bmc.2013.12.055

Abstract

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.

Keywords

Hedgehog signaling pathway; Inhibitors; Novel; Pyrrolo[2,1-f][1,2,4]triazine.

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