ABSTRACT
Numerous studies suggest that the majority of amyloid-ß (Aß) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Aß (pE-Aß, including N3pE-Aß40/42 and N11pE-Aß40/42) 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-Aß 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 Aß 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.
Subject(s)
Alzheimer Disease/drug therapy , Aminoacyltransferases/antagonists & inhibitors , Benzimidazoles/therapeutic use , Enzyme Inhibitors/therapeutic use , Imidazolines/therapeutic use , Nootropic Agents/therapeutic use , Alzheimer Disease/psychology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/drug effects , Animals , Benzimidazoles/cerebrospinal fluid , Benzimidazoles/pharmacokinetics , Binding Sites , Cyclization , Drug Delivery Systems , Enzyme Inhibitors/cerebrospinal fluid , Enzyme Inhibitors/pharmacokinetics , Female , HEK293 Cells , Humans , Imidazolines/cerebrospinal fluid , Imidazolines/pharmacokinetics , Male , Maze Learning/drug effects , Mice , Mice, Transgenic , Nootropic Agents/cerebrospinal fluid , Nootropic Agents/pharmacokinetics , Protein Binding , Rats , Spatial Learning/drug effectsABSTRACT
Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.