Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase

Wesley C. Van Voorhis, Kasey L. Rivas, Pravin Bendale, Laxman Nallan, Carolyn Hornéy, Lynn K. Barrett, Kevin D. Bauer, Brian P. Smart, Sudha Ankala, Oliver Hucke, Christophe L M J Verlinde, Debopam Chakrabarti, Corey Strickland, Kohei Yokoyama, Frederick S. Buckner, Andrew Hamilton, David K. Williams, Louis J. Lombardo, David Floyd, Michael H. Gelb

Research output: Contribution to journalArticle

Abstract

New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the 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 these tests were followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when it was given orally to P. berghei-infected rats every 8 h for a total of 72 h. However, PB-93 was rapidly cleared, and dosing every 12 h failed to cure the rats. Thus, the in vivo results corroborate the in vitro pharmacodynamics and demonstrate that 72 h of continuous high-level exposure to PFTIs is necessary to kill plasmodia. The metabolism of PB-93 was demonstrated by a novel technique that relied on double labeling with a 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-methyl-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-methyl-imidazole from dealkylation.

Original languageEnglish (US)
Pages (from-to)3659-3671
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume51
Issue number10
DOIs
StatePublished - Oct 2007

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Plasmodium falciparum
Pharmacokinetics
Liver Microsomes
Dealkylation
Caco-2 Cells
Plasmodium
Intestinal Absorption
Antimalarials
Liquid Chromatography
Isotopes
Biological Availability
p21(ras) farnesyl-protein transferase
1,2,3,4-tetrahydroquinoline
Rodentia
Permeability
Mass Spectrometry
X-Rays
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Van Voorhis, W. C., Rivas, K. L., Bendale, P., Nallan, L., Hornéy, C., Barrett, L. K., ... Gelb, M. H. (2007). Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase. Antimicrobial Agents and Chemotherapy, 51(10), 3659-3671. https://doi.org/10.1128/AAC.00246-07

Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase. / Van Voorhis, Wesley C.; Rivas, Kasey L.; Bendale, Pravin; Nallan, Laxman; Hornéy, Carolyn; Barrett, Lynn K.; Bauer, Kevin D.; Smart, Brian P.; Ankala, Sudha; Hucke, Oliver; Verlinde, Christophe L M J; Chakrabarti, Debopam; Strickland, Corey; Yokoyama, Kohei; Buckner, Frederick S.; Hamilton, Andrew; Williams, David K.; Lombardo, Louis J.; Floyd, David; Gelb, Michael H.

In: Antimicrobial Agents and Chemotherapy, Vol. 51, No. 10, 10.2007, p. 3659-3671.

Research output: Contribution to journalArticle

Van Voorhis, WC, Rivas, KL, Bendale, P, Nallan, L, Hornéy, C, Barrett, LK, Bauer, KD, Smart, BP, Ankala, S, Hucke, O, Verlinde, CLMJ, Chakrabarti, D, Strickland, C, Yokoyama, K, Buckner, FS, Hamilton, A, Williams, DK, Lombardo, LJ, Floyd, D & Gelb, MH 2007, 'Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase', Antimicrobial Agents and Chemotherapy, vol. 51, no. 10, pp. 3659-3671. https://doi.org/10.1128/AAC.00246-07
Van Voorhis, Wesley C. ; Rivas, Kasey L. ; Bendale, Pravin ; Nallan, Laxman ; Hornéy, Carolyn ; Barrett, Lynn K. ; Bauer, Kevin D. ; Smart, Brian P. ; Ankala, Sudha ; Hucke, Oliver ; Verlinde, Christophe L M J ; Chakrabarti, Debopam ; Strickland, Corey ; Yokoyama, Kohei ; Buckner, Frederick S. ; Hamilton, Andrew ; Williams, David K. ; Lombardo, Louis J. ; Floyd, David ; Gelb, Michael H. / Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase. In: Antimicrobial Agents and Chemotherapy. 2007 ; Vol. 51, No. 10. pp. 3659-3671.
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