title: Discovery of novel 4-(2-pyrimidinylamino)benzamide derivatives as highly potent and orally available hedgehog signaling pathway inhibitors.
abstract: A series of novel hedgehog signaling pathway inhibitors have been designed by structural modification based on the former reported scaffold of 4-(2-pyrimidinylamino)benzamide. The SAR for this series was described and many derivatives showed potent inhibitory activity. Among these compounds, compounds 12af and 12bf were identified to have high potency and optimal PK profiles. Although both of compounds 12af and 12bf did not show strong antitumor efficacy in LS-174T nude mice model, they were promising candidates as Hh signaling inhibitors due to great potency against Hh signaling pathway and outstanding PK properties, deserving further evaluation in other Hh signaling operative tumor models.
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: 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: Feng
authors.initials: F
authors.lastname: Tang
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: Liyun
authors.initials: L
authors.lastname: Gu
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: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000284:Administration, Oral; D000586:Amination; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D053823:Hedgehog Proteins; D011725:Pyridines
keywords: 4-(2-pyrimidinylamino)benzamide; Hedgehog signaling pathway inhibitors; In vivo; SAR