ABSTRACT: The amyloid-? peptide (A?)-in particular, the 42-amino acid form, A?1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit A? synthesis or increase the clearance of A? have entered clinical trials, including ?-secretase inhibitors, anti-A? antibodies, and amyloid-? precursor protein cleaving enzyme inhibitors. A unique class of small molecules, ?-secretase modulators (GSMs), selectively reduce A?1-42 production, and may also decrease A?1-40 while simultaneously increasing one or more shorter A? peptides, such as A?1-38 and A?1-37. GSMs are particularly attractive because they do not alter the total amount of A? peptides produced by ?-secretase activity; they spare the processing of other ?-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, ?-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 A?1-42 and A?1-40 levels while increasing A?1-38 and A?1-37 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.
