ABSTRACT
Reducing the production of larger aggregation-prone amyloid ß-peptides (Aß) remains an untested therapeutic approach for reducing the appearance and growth of Aß plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aß peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aß42, increased the levels of Aß38 and had little effect on the levels of Aß40, the most abundant Aß species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aß42 levels and Aß plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aß42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.
Subject(s)
Aldehydes/pharmacokinetics , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Brain/drug effects , Brain/enzymology , Aldehydes/administration & dosage , Amyloid beta-Peptides/blood , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Macaca fascicularis , Male , Mice , Plaque, Amyloid/metabolism , Protein Isoforms/blood , Rats , Rats, Inbred F344ABSTRACT
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aß42 levels in mice and rats.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Enzyme Inhibitors/chemistry , Phenylacetates/chemistry , Piperidines/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Brain/metabolism , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Mice , Peptide Fragments/metabolism , Phenylacetates/chemical synthesis , Phenylacetates/pharmacokinetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , RatsABSTRACT
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aß42, increased Aß38, but had little to no effect on Aß40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aß42 levels in CF-1 mice and Fischer rats, as well as plasma Aß42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
