title: Synthesis and pharmacological evaluation of trifluoromethyl containing 4-(2-pyrimidinylamino)benzamides as Hedgehog signaling pathway inhibitors.
abstract: In present study, a series of novel containing trifluoromethyl 4-(2-pyrimidinylamino)benzamide derivatives were designed by the fluorine scan strategy. Their Hh signaling inhibitory activities were evaluated by Gli-luciferase reporter method. The comprehensive SAR was discussed and several derivatives were found to display more potent Hh signaling inhibitory activity than positive drug vismodegib. Compound 13d was the most potent compound with IC50 of 1.44nM against Hh signaling pathway and also exhibited optimal PK properties in the in vivo PK properties study, deserved as an ideal lead compound for further study in future.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China. Electronic address: xmhcpu@163.com.
authors.forename: Minhang
authors.initials: M
authors.lastname: Xin
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wen
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Xinge
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
mesh_terms: D000586:Amination; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054879:Halogenation; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D041681:NIH 3T3 Cells; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000813:Anilides; D001549:Benzamides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D011743:Pyrimidines
keywords: 4-(2-Pyrimidinylamino)benzamide; Hedgehog signaling pathway inhibitors; In vivo; SAR; Trifluoromethyl