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

Autor:	Toyn JH; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Thompson LA; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Lentz KA; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Meredith JE Jr; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Burton CR; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Sankaranararyanan S; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Guss V; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Hall T; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; Preclinical Sciences, Alexion Pharmaceuticals, Inc 352 Knotter Drive, Cheshire, CT 06410, USA., Iben LG; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Krause CM; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Krause R; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Lin XA; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Pierdomenico M; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Polson C; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Robertson AS; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Denton RR; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Grace JE; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Morrison J; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Raybon J; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Zhuo X; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Snow K; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Padmanabha R; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Agler M; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; High Throughput Biology, Boehringer Ingelheim, 900 Ridgebury Road, Ridgefield, CT 06877, USA., Esposito K; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Harden D; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Prack M; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Varma S; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; Stratford High School, 45 North Parade, Stratford, CT 06615, USA., Wong V; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; External Research Solutions, WWMC, Pfizer World Wide Research & Development, Eastern Point Road, Groton, CT 06340, USA., Zhu Y; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; Arvinas Inc, 5 Science Park, New Haven, CT 06511, USA., Zvyaga T; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Gerritz S; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Marcin LR; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Higgins MA; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Shi J; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Wei C; Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA ; Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer World Wide Research & Development, Eastern Point Road, Groton, CT 06340, USA., Cantone JL; Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Drexler DM; Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Macor JE; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Olson RE; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Ahlijanian MK; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA., Albright CF; Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Jazyk:	angličtina
Zdroj:	International journal of Alzheimer's disease [Int J Alzheimers Dis] 2014; Vol. 2014, pp. 431858. Date of Electronic Publication: 2014 Jul 08.
DOI:	10.1155/2014/431858
Abstrakt:	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.
Databáze:	MEDLINE
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