Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780. (7th July 2014) - Toyn, Jeremy H.
Abstract : Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid- β peptide (A β ), particularly the 42-amino acid A β 1-42, in the brain. A β 1-42 levels can be decreased by γ -secretase modulators (GSM), which are small molecules that modulate γ -secretase, an enzyme essential for A β production. BMS-869780 is a potent GSM that decreased A β 1-42 and A β 1-40 and increased A β 1-37 and A β 1-38, without inhibiting overall levels of A β peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ -secretase and lowered brain A β 1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and A β 1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust A β 1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain A β 1-42 without Notch-related side effects.