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P3‐300: Identification of an oral pharmaceutical known to penetrate the CNS that inhibits the formation of Aβ oligomers in vitro
Author(s) -
Moore Susan,
Dealler Stephen,
Wilson Stuart,
Huckerby Thomas,
Allsop David
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.971
Subject(s) - oligomer , fibril , thioflavin , chemistry , senile plaques , in vitro , pathogenesis , drug , amyloid (mycology) , genetically modified mouse , biophysics , biochemistry , pharmacology , transgene , alzheimer's disease , disease , medicine , biology , pathology , organic chemistry , inorganic chemistry , gene
cellular BACE-1 and excellent oral properties. In this study, we demonstrate that CTS21166 penetrates the brain and reduces central soluble Ab in continuously sampled ventricular CSF in rats. Methods: CTS21166 was administered by various routes to male Sprague-Dawley rats. At various times post-dose, brain, CSF, and plasma were sampled. Ventricular CSF was sampled continuously by a microdialysis probe (CMA Microdialysis, Sweden) placed into the lateral ventricle. Concentration of Ab40 was measured by ELISA (WAKO Chemicals, USA, Inc.). Concentration of CTS21166 in CSF, plasma and brain was determined by LC/MS. Results: Single dose administration of CTS21166 reduced central Ab40 in rats by greater than 50%. Differences in the magnitude of Ab40 reduction were observed in various CSF compartments. The spatial and temporal difference in Ab40 reduction in brain and CSF compartments suggests equilibrium between Ab40 produced centrally and in more distal CSF compartments. The CTS21166 exposure in brain associated with reduction of Ab40 from single and multiple dosing in rats was confirmed. CTS21166 displayed excellent brain penetration in multiple nontransgenic species including mice, rats, dogs and monkeys. Conclusions: CTS21166 reduced soluble Ab40 in brain and CSF of rats following single or multiple dosing. Differential efficacy in each compartment may be due to proximity to the site of BACE-1 inhibition and pulsed Ab equilibration in each compartment determined by the clearance rate of Ab existing prior to administration of the BACE-1 inhibitor CTS21166.