Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575).
A previous study by us suggests the utility of cerebrospinal fluid (CSF) and plasma Abeta as biomarkers of beta- or gamma-secretase inhibition. The present study characterized further Abeta pharmacodynamics in these tissues from Tg2576 mice and examined their correlation with brain Abeta after acute treatment with a potent gamma-secretase inhibitor, N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY-411575). A single dose of LY-411575 dose-dependently (0.1-10 mg/kg p.o.) reduced Abeta(1-40) and Abeta(1-42) in the CSF and the brain. In contrast, plasma Abeta levels were increased by 0.1 mg/kg LY-411575 and were followed by a dose-dependent reduction at higher doses. The time courses of Abeta reduction and recovery were distinct for the three tissues: maximal declines in Abeta levels were evident by 3 h in the CSF and plasma but not until 9 h in the brain. A recovery in Abeta levels was underway in the CSF by 9 h and nearly completed by 24 h in all tissues. The differential time courses in the three compartments do not seem to be due to pharmacokinetic factors. Five days of twice-daily treatment with LY-411575 not only sustained the Abeta reductions in all tissues but also significantly augmented the efficacy in the brain and plasma. The increased efficacy occurred in the absence of compound accumulation and was consistent with the recovery rates in each compartment. Overall, Abeta in the CSF and not plasma seems to be a better biomarker of brain Abeta reduction; however, the time course of Abeta changes needs to be established in clinical studies.
Lanz
Thomas A
TA
Pfizer Inc., Eastern Point Road, MS# 8220-4183, Groton, CT 06340, USA. thomas.a.lanz@pfizer.com
Hosley
John D
JD
Adams
Wade J
WJ
Merchant
Kalpana M
KM
D000409:Alanine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001381:Azepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D058225:Plaque, Amyloid; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D000409:Alanine