New class of azaheptapyridine FPT inhibitors as potential cancer therapy agents Hugh Y. Zhu ⇑ , Jagdish Desai, Alan B. Cooper, James Wang, Dinananth F. Rane, Paul Kirschmeier, Corey Strickland, Ming Liu, Amin A. Nomeir, Viyyoor M. Girijavallabhan Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA article info Article history: Received 1 November 2013 Revised 10 December 2013 Accepted 11 December 2013 Available online 2 January 2014 Keyword: FPT inhibitors abstract 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 exhib- ited potent enzyme (IC 50 = 1.4 nM) and cellular activities (soft agar IC 50 = 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. Ó 2013 Elsevier Ltd. All rights reserved. Farnesyl protein transferase (FPT) was an attractive oncology target. It was postulated that by blocking ras oncogene post trans- lational farnesylation modification, downstream signaling of uncontrolled growth would be stopped. FPT inhibitors therefore had been widely studied and were the subject of numerous publi- cations. Several FTI (FPT inhibitor) compounds were evaluated in clinic and had shown some promising anti-tumor activity. 1 Re- cently, a FTI was shown to reverse accumulation of farnesylated prelamin A. The compound was effective in mouse model of proge- ria, a devastating disease characterized with premature aging. 2 More recently, there has been some interest in using FPT inhibitors in neurodegenerative disease (Parkinson disease) through blocking UCH-L1 farnesylation. 3 Herein, we report discovery of tertiary hy- droxyl class of potent FPT inhibitors in our general C-imidazole FPT bridgehead azaheptapyridine series. In an earlier communication, we disclosed a series of potent FPT inhibitors with C-linked imidazole at bridgehead of azaheptapyri- dine scaffold. 4 Bridgehead imidazole motif binds to zinc at the ac- tive site and provided great improvement in enzyme and cellular activities. At the methylene linker, we demonstrated tolerability of a variety of substitutions. It allowed us to introduce polar groups to reduce hERG activity. One of the compounds, 1, had an attractive profile with FPT IC 50 = 0.3 nM and blocked cell growth in soft agar with IC 50 = 0.5 nM. It had reasonable rat PK with an AUC (0–6 h) of 2.57 lM h at 10 mpk (hERG IC 50 >1 lM) (Fig. 1). Compound 1 had a secondary hydroxyl group at the bridgehead benzylic position. It was suspected that this OH group could be oxi- dized in vivo and resulted in scrambling of the stereochemistry. In- deed, detailed rat PK study confirmed that 1 could be converted to ketone 2 (FPT IC 50 >18 nM) which was subsequently reduced to less active isomer 3 (FPT IC 50 = 12 nM). We set out to address this problem by introducing alkyl groups to block oxidation of bridgehead benzylic position. The initial synthesis started with vinyl bromide 4 which underwent Li–Br exchange with 2 equiv of BuLi followed by addition of N1-methyl 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.12.046 ⇑ Corresponding author. E-mail address: hughzhu@hotmail.com (H.Y. Zhu). N Cl N N O O N N O N Cl N N O O N N N Cl N N O O N N OH OH 1 2 3 Figure 1. In vivo scrambling of secondary OH of 1. Bioorganic & Medicinal Chemistry Letters 24 (2014) 1228–1231 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl