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International Journal of Alzheimer’s Disease
Volume 2014, Article ID 431858, 22 pages
http://dx.doi.org/10.1155/2014/431858
Research Article

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

1Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
2Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
3Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
4Preclinical Sciences, Alexion Pharmaceuticals, Inc 352 Knotter Drive, Cheshire, CT 06410, USA
5Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
6High Throughput Biology, Boehringer Ingelheim, 900 Ridgebury Road, Ridgefield, CT 06877, USA
7Stratford High School, 45 North Parade, Stratford, CT 06615, USA
8External Research Solutions, WWMC, Pfizer World Wide Research & Development, Eastern Point Road, Groton, CT 06340, USA
9Arvinas Inc, 5 Science Park, New Haven, CT 06511, USA
10Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
11Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer World Wide Research & Development, Eastern Point Road, Groton, CT 06340, USA

Received 28 March 2014; Accepted 18 May 2014; Published 8 July 2014

Academic Editor: George Perry

Copyright © 2014 Jeremy H. Toyn et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.