B1OORGANIC & MEDICINAL CHEMISTRY LETTERS Bioorganic & Medicinal Chemistry Letters 9 (1999) 1069-1074 Pergamon POTENT AND ORALLY BIOAVAILABLE NONCYSTEINE-CONTAINING INHIBITORS OF PROTEIN FARNESYLTRANSFERASE David J. Augeri,* Dave Janowick, Douglas Kalvin, Gerry Sullivan, John Larsen, Daniel Dickman, Hong Ding, Jerry Cohen, Jang Lee, Robert Warner, Peter Kovar, Sajeev Cherian, Badr Saeed, Haichao Zhang, Steve Tahir, Shi-Chung Ng, Hing Sham, and Saul H. Rosenberg Departments of Cancer Research and Combinatorial Chemistry, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, U.S.A. Received 9 December 1998; accepted 24 February 1999 Abstract: Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 rum in vitro (FTase) and is 32% bioavallable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs. © 1999Elsevier ScienceLtd. All rights reserved. Oncogenic Ras proteins are found in 20-30% of all human tumors including those of the lung (30%), colon (50%), and pancreas (90%). 1 Mutated Ras proteins are constitutively active and promote uncontrolled cell division. 2 The Ras protein is functional only after undergoing a series of posttranslational modifications. Famesylation of a cysteine residue near the C-terminus by the enzyme famesyltransferase (FTase) is required for membrane association and signal transduction. Inhibition of FTase will render Ras inactive and block the uncontrolled mitogenic signaling pathway. 3-7 Several structurally distinct classes of farnesyltransferase inhibitors are known, s The first reported inhibitors were designed to mimic the Ras C-terminal tetrapeptide (CVFM), which is the minimum recognition sequence. FTI-276 is an example of this class of inhibitors where the central two amino acids have been successfully replaced by a hydrophobic biphenyl core and are flanked by cysteine and methionine. 9'~° Figure 1 HS H °<'s FTI-276 Me 'SMe IC5o FTase = 0.5 nM IC5o FTase = 0.4 nM We recently reported the transformation of FTI-276 into the potent noncysteine-containing FTase inhibitor 1 (Figure 1). ~ Although 1 proved to be potent in vitro and active in whole cells as the methionine acid, it displayed poor bioavailability. Earlier, we observed that phenyl ether 2 displayed significantly better absorption characteristics than the corresponding pyridyl ether, albeit at a great cost in potency (IC5o pyridyl ether = 4.0 nM, 2 = >1 ktM, Figure 2). However, it answered an important question concerning bioavailability. It was clear that the pyridyl ether moiety posed a pharmacokinetic liability. 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00144-4