Identification and Preclinical Pharmacology of theγ-Secretase Modulator BMS-869780

Abstract

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 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 Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 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 Aβ1-42 without Notch-related side effects.

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

“…One of their lead compounds, 31 (BMS-869780),105 has been described as their first optimized candidate. This GSM replaces the typical methyl imidazole with a chloroimidazole.…”

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

“…The novel GSMs BMS-932481 and BMS-986133 were prepared at Bristol-Myers Squibb, Wallingford, CT, using methods reported in Bristol-Myers Squibb patents ( Boy et al 2014a , b ). The γ -secretase inhibitors (GSIs) used for comparisons in some experiments, (R)-4-(2-(1-((4-chloro-N-(2,5-difluorophenyl)phenyl)sulfonamido)ethyl)-5-fluorophenyl)butanoic acid (BMS-299897; Barten et al, 2005 ) and (R)-2-((4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenyl)sulfonamido)-3-cyclopropylpropanamide (BMS-698861; Toyn et al, 2014 ), have been described previously.…”

“…In overview, A β peptides were quantified using a range of different immunoassays, using antibodies that are specific for the free C-terminal amino acids of A β 1-42, A β 1-40, A β 1-38, or A β 1-37 ( Toyn et al, 2014 ). Immunoassays for A β 1-x used antibodies that are not selective for the free C-terminal amino acid, and therefore measured the sum of the A β peptides including A β 1-42, A β 1-40, A β 1-38, and A β 1-37.…”

“…(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) are novel bicyclic pyrimidines ( Supplemental Fig. 1 ) related to analogs that were initially identified in a high-throughput screen ( Toyn et al, 2014 ). Here, we show that GSM mechanism and A β -lowering activity exhibit excellent translation across species.…”

Structural and Chemical Biology of Presenilin Complexes

“…AstraZeneca has published structurally related GSMs including AZ4800, which has an Ab42 IC 50 of 26 nM and lowered brain Ab42 by 46% when dosed orally at 130 mg/kg (Borgegard et al 2012). BMS incorporated an aminotriazole core and a chloroimidazole A-ring in place of the commonly used 4-methylimidazole to afford potent GSMs such as BMS-869780 (Ab42 IC 50 ¼ 5.6 nM) (Toyn et al 2014). PK/PD modeling indicated that a dose of 700 mg would be required to achieve a 25% reduction of Ab42 in the human brain.…”