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

Toyn JH, Thompson LA, Lentz KA, Meredith JE, Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, Krause CM, Krause R, Lin XA, Pierdomenico M, Polson C, Robertson AS, Denton RR, Grace JE, Morrison J, Raybon J, Zhuo X, Snow K, Padmanabha R, Agler M, Esposito K, Harden D, Prack M, Varma S, Wong V, Zhu Y, Zvyaga T, Gerritz S, Marcin LR, Higgins MA, Shi J, Wei C, Cantone JL, Drexler DM, Macor JE, Olson RE, Ahlijanian MK, Albright CF - Int J Alzheimers Dis (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

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.

No MeSH data available.


Related in: MedlinePlus

(a) Chemical structures of the compounds used in this study are shown. (b) Overview of the HTS and subsequent triage of compounds summarizes experimentation steps in boxes, with outcomes indicated beside the arrows. Costs of reagents and disposables were a major consideration in the design, particularly the initial screen of 106 samples. (c) Principle of the Aβ1-42 immunoassay; simultaneous binding of monoclonal antibody conjugates 252-APC and 565-Eu (specific for C-terminus of Aβ1-42) to Aβ1-42 leads to FRET-based emission at 665 nm. The ratio of emission at 665 nm to fluorescence at 615 nm represents the level of Aβ1-42 in the sample. (d) Principle of the Aβ1-40 immunoassay; same as described above for the Aβ1-42 immunoassay, except that the monoclonal antibody conjugate TSD-Eu (specific for C-terminus of Aβ1-40) was used in place of 565-Eu.
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Related In: Results  -  Collection


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fig1: (a) Chemical structures of the compounds used in this study are shown. (b) Overview of the HTS and subsequent triage of compounds summarizes experimentation steps in boxes, with outcomes indicated beside the arrows. Costs of reagents and disposables were a major consideration in the design, particularly the initial screen of 106 samples. (c) Principle of the Aβ1-42 immunoassay; simultaneous binding of monoclonal antibody conjugates 252-APC and 565-Eu (specific for C-terminus of Aβ1-42) to Aβ1-42 leads to FRET-based emission at 665 nm. The ratio of emission at 665 nm to fluorescence at 615 nm represents the level of Aβ1-42 in the sample. (d) Principle of the Aβ1-40 immunoassay; same as described above for the Aβ1-42 immunoassay, except that the monoclonal antibody conjugate TSD-Eu (specific for C-terminus of Aβ1-40) was used in place of 565-Eu.

Mentions: The GSM, BMS-869780 [54, 55], and the GSIs BMS-299897 [56] and BMS-433796 [57] have been reported previously. The GSI BMS-698861 is described in a BMS patent [58]. Chemical structures are shown in Figure 1(a).


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

Toyn JH, Thompson LA, Lentz KA, Meredith JE, Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, Krause CM, Krause R, Lin XA, Pierdomenico M, Polson C, Robertson AS, Denton RR, Grace JE, Morrison J, Raybon J, Zhuo X, Snow K, Padmanabha R, Agler M, Esposito K, Harden D, Prack M, Varma S, Wong V, Zhu Y, Zvyaga T, Gerritz S, Marcin LR, Higgins MA, Shi J, Wei C, Cantone JL, Drexler DM, Macor JE, Olson RE, Ahlijanian MK, Albright CF - Int J Alzheimers Dis (2014)

(a) Chemical structures of the compounds used in this study are shown. (b) Overview of the HTS and subsequent triage of compounds summarizes experimentation steps in boxes, with outcomes indicated beside the arrows. Costs of reagents and disposables were a major consideration in the design, particularly the initial screen of 106 samples. (c) Principle of the Aβ1-42 immunoassay; simultaneous binding of monoclonal antibody conjugates 252-APC and 565-Eu (specific for C-terminus of Aβ1-42) to Aβ1-42 leads to FRET-based emission at 665 nm. The ratio of emission at 665 nm to fluorescence at 615 nm represents the level of Aβ1-42 in the sample. (d) Principle of the Aβ1-40 immunoassay; same as described above for the Aβ1-42 immunoassay, except that the monoclonal antibody conjugate TSD-Eu (specific for C-terminus of Aβ1-40) was used in place of 565-Eu.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4109680&req=5

fig1: (a) Chemical structures of the compounds used in this study are shown. (b) Overview of the HTS and subsequent triage of compounds summarizes experimentation steps in boxes, with outcomes indicated beside the arrows. Costs of reagents and disposables were a major consideration in the design, particularly the initial screen of 106 samples. (c) Principle of the Aβ1-42 immunoassay; simultaneous binding of monoclonal antibody conjugates 252-APC and 565-Eu (specific for C-terminus of Aβ1-42) to Aβ1-42 leads to FRET-based emission at 665 nm. The ratio of emission at 665 nm to fluorescence at 615 nm represents the level of Aβ1-42 in the sample. (d) Principle of the Aβ1-40 immunoassay; same as described above for the Aβ1-42 immunoassay, except that the monoclonal antibody conjugate TSD-Eu (specific for C-terminus of Aβ1-40) was used in place of 565-Eu.
Mentions: The GSM, BMS-869780 [54, 55], and the GSIs BMS-299897 [56] and BMS-433796 [57] have been reported previously. The GSI BMS-698861 is described in a BMS patent [58]. Chemical structures are shown in Figure 1(a).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Exploratory Biology and Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

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.

No MeSH data available.


Related in: MedlinePlus