Robust Translation of  -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

Abstract

The amyloid-β peptide (Aβ)—in particular, the 42–amino acid form, Aβ1-42—is thought to play a key role in the pathogenesis of Alzheimer’s disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

“…In vivo, BMS-932481 exhibited dose-dependent A β 42 and A β 40 lowering in both the brain and CSF in rats and dogs (see Toyn et al, 2016 for a detailed discussion on preclinical pharmacology). The chemical structure of BMS-932481 is depicted in Fig.…”

“…1C ). CSF A β peptides were used as a surrogate for brain A β lowering and preclinical data demonstrated excellent correlation between the degree of brain and CSF A β lowering (see Toyn et al, 2016 for a detailed description of the CSF and brain A β -lowering relationship).…”

“…BMS-932481, a non-NSAID bicyclic pyrimidine, was developed as a selective GSM that showed selectivity for A β 40 and A β 42 reduction while sparing total A β levels both in vitro and in preclinical models and after single doses in CSF of normal healthy volunteers (see companion paper, Toyn et al, 2016 ). Our studies examined the effects of BMS-932481 on the safety, tolerability, pharmacokinetics, and pharmacodynamics in young and elderly healthy volunteers.…”

Bridging the Gap Between Fluid Biomarkers for Alzheimer’s Disease, Model Systems, and Patients

“…γ-secretase modulators have proven especially useful as therapeutic candidates because they do not alter the total amount of Aβ peptides produced by γ-secretase activity, instead, they spare the products of other γ-secretase processing, such as notch ( Toyn et al, 2016 ). Importantly, these compounds do not accelerate the production of the potentially toxic product BACE1-C-terminal fragment (C99) ( Toyn et al, 2016 ). In all species, research suggests that γ-secretase modulator treatment decrease Aβ42 and Aβ40 levels while increasing Aβ38 and Aβ37 by a corresponding amount.…”

“…In all species, research suggests that γ-secretase modulator treatment decrease Aβ42 and Aβ40 levels while increasing Aβ38 and Aβ37 by a corresponding amount. Therefore, the mechanism of action of γ-secretase modulators may translate well across species, validating its therapeutic strategy for utility in AD ( Toyn et al, 2016 ).…”