KP544, a nerve growth factor amplifier: Pharmacokinetics, safety, and efficacy in the rat

Thomas A. Krenitsky, John Dillberger, Elena Zotova, Joseph C. Arezzo, James B. Koprich, Farzad Mortazavi, Timothy A. Gates, Gary L. Dunbar

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5 Scopus citations

Abstract

In cultured cells, KP544 [2-amino-5-(4-chlorophenylethynyl)-4-(4-trans- hydroxycyclohexyl amino) pyrimidine] amplifies differentiation initiated by nerve growth factor (NGF) or cAMP. This report describes the pharmacokinetics, safety, and neuroprotective efficacy of KP544 in rats. After an oral dose of 10 mg/kg KP544 was 25% bioavailable with a plasma half-life of 1.3 h and brain levels 6-fold higher than plasma levels at 4 and 8 h post-dose. In a safety study, daily oral dosing for 30 days at 10 and 100 mg/kg was well tolerated. The favorable pharmacokinetic and safety profiles, together with its amplification of NGF in vitro, prompted evaluation of KP544 in two models involving NGF deficiencies. In the first model, brains were lesioned with intrastriatal injections of quinolinic acid. KP544 at oral doses of 0.02 to 1.0 mg/ kg/day almost completely prevented the resulting learning deficits as evaluated using a radial-arm-water maze. At the lowest dose, there was a slower onset of functional improvement. These effects were accompanied by reductions (16-34%) in the striatal lesion size that were greatest at the highest dose and comparable to those seen with NGF therapy. The second model involved a peripheral neuropathy induced by taxol that is associated with decreases in NGF. KP544 at oral doses of 0.1-10 mg/kg/day decreased the severity of the neuropathy as measured by caudal nerve conduction velocities (30-70% return to control values). In both models, KP544 had a large therapeutic index suggesting its potential as a new approach for treating clinical disorders involving deficiencies in NGF.

Original languageEnglish (US)
Pages (from-to)60-70
Number of pages11
JournalDrug Development Research
Volume62
Issue number1
DOIs
StatePublished - May 1 2004

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Keywords

  • Alzheimer's disease
  • Huntington's disease
  • KP544
  • Nerve growth factor
  • Taxol

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Krenitsky, T. A., Dillberger, J., Zotova, E., Arezzo, J. C., Koprich, J. B., Mortazavi, F., Gates, T. A., & Dunbar, G. L. (2004). KP544, a nerve growth factor amplifier: Pharmacokinetics, safety, and efficacy in the rat. Drug Development Research, 62(1), 60-70. https://doi.org/10.1002/ddr.10384