New class of azaheptapyridine FPT inhibitors as potential cancer therapy agents

• Published in: Bioorganic & medicinal chemistry letters 2014-02, Vol.24 (4), p.1228-1231
• Main Authors: Zhu, Hugh Y, Desai, Jagdish, Cooper, Alan B, Wang, James, Rane, Dinananth F, Kirschmeier, Paul, Strickland, Corey, Liu, Ming, Nomeir, Amin A, Girijavallabhan, Viyyoor M
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Haplorhini; Humans; Mice; Mice, Transgenic; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.12.046

Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.