PT - JOURNAL ARTICLE AU - Torsten Hoffmann AU - Antje Meyer AU - Ulrich Heiser AU - Stephan Kurat AU - Livia Böhme AU - Martin Kleinschmidt AU - Karl-Ulrich Bühring AU - Birgit Hutter-Paier AU - Martina Farcher AU - Hans-Ulrich Demuth AU - Inge Lues AU - Stephan Schilling TI - Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy AID - 10.1124/jpet.117.240614 DP - 2017 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 119--130 VI - 362 IP - 1 4099 - http://jpet.aspetjournals.org/content/362/1/119.short 4100 - http://jpet.aspetjournals.org/content/362/1/119.full SO - J Pharmacol Exp Ther2017 Jul 01; 362 AB - Numerous studies suggest that the majority of amyloid-β (Aβ) peptides deposited in Alzheimer’s disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Aβ (pE-Aβ, including N3pE-Aβ40/42 and N11pE-Aβ40/42) 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 catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with Ki values ranging between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double-transgenic mice with 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 cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 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 cyclization compared with cyclization of physiologic 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.