Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors.
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.
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.
Minhang
M
Xin
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Liandi
L
Zhang
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.
Feng
F
Tang
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.
Chongxing
C
Tu
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Jun
J
Wen
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.
Xinge
X
Zhao
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Zhaoyu
Z
Liu
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.
Lingfei
L
Cheng
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Han
H
Shen
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006207:Half-Life; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007275:Injections, Intravenous; D011758:Pyrroles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
D001549:Benzamides; D053823:Hedgehog Proteins; C000591913:N-(2-methyl-5-(morpholinomethyl)phenyl)-4-((4-(4-(trifluoromethoxy)phenyl)pyrrolo(2,1-f)(1,2,4)triazin-2-yl)amino)benzamide; D011758:Pyrroles; D014227:Triazines
Hedgehog signaling pathway; Inhibitors; Novel; Pyrrolo[2,1-f][1,2,4]triazine