Abstract
Numerous studies suggest that the majority of Aβ peptides deposited in Alzheimer's Disease (AD) is truncated and post-translationally modified at the N-terminus. Among these modified species, pyroglutamyl-Aβ (pE-Aβ including N3pE-Aβ42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers and reduces degradation by peptidases leading ultimately to the accumulation of the peptide and progression of AD. It has been shown, that the formation of pyroglutamyl residues is catalysed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC-inhibitor PQ912, the first-in-class compound that is in clinical development. PQ912 inhibits human, rat and mouse QC-activity with Ki-values in the range between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double transgenic mice applying approximately 200 mg/kg/day via chow shows a significant reduction of pE-Aβ levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and CSF concentration of PQ912 which relates to a QC target occupancy of > 60 %. Thus, we conclude that > 50 % inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for Aβ cyclisation compared to cyclisation of physiological substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.
- The American Society for Pharmacology and Experimental Therapeutics