Antimicrob Agents Chemother. 2007 Jul 2; [Epub ahead of print]
Tetrahydroquinoline Plasmodium falciparum protein farnesyltransferase inhibitors: Efficacy, pharmacokinetics, and metabolism.
Van Voorhis WC, Rivas KL, Bendale P, Nallan L, Hornéy C, Barrett LK, Bauer KD, Smart BP, Ankala S, Hucke O, Verlinde CL, Chakrabarti D, Strickland C, Yokoyama K, Buckner FS, Hamilton AD, Williams DK, Lombardo LJ, Floyd D, Gelb MH.
Departments of Medicine, Chemistry, and Biochemistry, University of Washington, Seattle, WA 98195. Departments of Molecular Biology & Microbiology, University of Central Florida, Orlando, FL. Department of Structural Chemistry, Schering-Plough Research Institute, Kenilworth, NJ. Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06511. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ. Pharmacopeia Inc, Cranbury, NJ.
New anti-malarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against P. falciparum PFT and effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from circulation of rodents. In this paper, we validate both the Caco-2 cell permeability model for predicting THQ intestinal absorption and the in vitro liver microsome model for predicting THQ clearance in vivo. Incremental improvements in efficacy, oral absorption, and clearance rate were monitored by in vitro tests and followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when given orally to P. berghei-infected rats every 8 hours for a total of 72 hours. However PB-93 was rapidly cleared, and 12 hour dosing failed to cure rats. Thus, in vivo results corroborate in vitro pharmacodynamics and demonstrate that 72 hours of continuous high-level exposure of PFTIs is necessary to kill Plasmodia. PB-93 metabolism was demonstrated with a novel technique, relying on double labeling with radiolabel and heavy isotopes combined with radiometric liquid chromatography and mass spectrometry. The major liver microsome metabolite of PB-93 has the PFT Zn-binding N-Me-imidazole removed; this metabolite is inactive in blocking PFT function. By solving the X-ray crystal structure of PB-93 bound to rat PFT, a model of PB-93 bound to malarial PFT was constructed. This model suggests areas of the THQ PFTIs that can be modified to retain efficacy and protect the Zn-binding N-Me-imidazole from dealkylation. |
