Aryl Tetrahydropyridine Inhibitors of Farnesyltransferase: Bioavailable Analogues with Improved Cellular Potency StephenL.Gwaltney,II,* StephenJ.O’Connor,LissaT.J.Nelson,GerardM.Sullivan, HovisImade,WeiboWang,LisaHasvold,QunLi,JeromeCohen,Wen-ZhenGu, StephenK.Tahir,JoyBauch,KennanMarsh,Shi-ChungNg,DavidJ.Frost, Haiying Zhang, Steve Muchmore, Clarissa G. Jakob, Vincent Stoll, Charles Hutchins, SaulH.RosenbergandHingL.Sham Pharmaceutical Discovery, R47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA Received 12 August 2002; accepted 2 January 2003 Abstract—Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bio- available aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed. # 2003ElsevierScienceLtd.Allrightsreserved. In the preceding paper, we described the discovery of a novel class of farnesyltransferase inhibitors (FTIs) that contain a tetrahydropyridine (THP) core. In this letter, we disclose further examples from this series, many of whicharepotentinacellularassayandseveralofwhich are bioavailable. As explained before, we sought a selective inhibitor of FT. Initially, all our compounds weretestedfortheirabilitytoinhibitFTandGGT-Iin vitro. Potent compounds were then tested in a cellular assay that measured inhibition of the farnesylation of Ras (Ras processing, RP). 1 Selected compounds were then tested for pharmacokinetics. 2 The best compound identified in the previous work is the histidine derivative 1 (Fig. 1). This compound is potent and selective for FT, but suffers loss of potency inthecellularassay. In an effort to improve upon this compound, we exam- ined several other series of tetrahydropyridine contain- ing FTIs. One series related to the previously described glycinederivativesisrepresentedbytheureasin Scheme 1. The synthesis of these analogues begins with the known compounds 2 and 3. Reductive amination pro- vided secondary amine 4. In situ formation of the car- bamoyl chloride followed by addition of the tetrahydropyridine core gave the urea. These lower homologues of the glycine derivatives show markedly improved potency for FT inhibition. These compounds are also selective for FT over the related enzyme ger- anylgeranyltransferase-I (GGT-I). Unfortunately, none of these compounds was sufficiently potent in the cel- lular assay. Wenextpreparedananaloguewithaonecarbonlinker attaching the imidazole and cyanophenyl pharmaco- phores to the tetrahydropyridine core. This compound waspreparedbyalkylatingtheTHPwiththesecondary chloride derived from 11. 12 demonstrated excellent potency for farnesyltransferase and was also potent in the cellular assay, but was not as selective as previous compounds(Scheme2). To examine a homologue of compound 12,wefoundit convenient to install a hydrazine unit in our inhibitor. The synthesis of this compound is shown in Scheme 3 and makes use of the method developed for the 0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00094-5 Bioorganic & Medicinal Chemistry Letters 13 (2003) 1363–1366 Figure 1. Compound 1. *Corresponding author. Tel.: +1-858-731-3562; fax: +1-858-550- 0526; e-mail: stephen.gwaltney@syrrx.com