Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors

• Published in: European journal of medicinal chemistry 2015-01, Vol.89, p.581-596
• Main Authors: Yang, Weimin, Chen, Yadong, Zhou, Xiang, Gu, Yazhou, Qian, Wenqi, Zhang, Fan, Han, Wei, Lu, Tao, Tang, Weifang
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antitumor agents; B-Raf inhibitors; Benzamides - chemistry; Cell Line, Tumor; Cell Proliferation - drug effects; DFG-Out; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Purines - chemistry; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.10.039

By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-RafV600E inhibitors. Among them, 20c–e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-RafV600E) cell lines with IC50 values of 3.190, 2.276, 1.856, 1.632 μM and 1.839 μM, respectively, comparable with the positive control Vemurafenib (IC50 = 3.32 μM). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-RafV600E) and SK-MEL-2 (B-RafWT) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-RafV600E) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-RafWT). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss. A series of 2-amino-3-purinylpyridine derivatives were synthesized and screened against B-RafV600E and A375 cell line, leading to the discovery of compound 20g, which exhibited potent A375 antiproliferative effects in vivo. [Display omitted] •Compound 6a was designed by combining the scaffolds of UI-125 and Sorafenib.•SAR was explored from the 2-amino-3-purinylpyridine derivatives.•All compounds have B-RafV600E inhibitory activities at nanomolar ranges.•Some compounds showed potent antiproliferation against melanoma A375 cell line.•Compound 20g displayed promising antitumor efficacy in vivo.