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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

BMS-869780 caused PXR activation in vitro and lipidosis in rat liver. (a) PXR activation in the presence of BMS-869780 was evaluated in HepG2 cell cultures using a luciferase transcriptional reporter construct (●), or by assay of CYP3A4 mRNA levels in primary human hepatocyte (PHH) cultures from two individual donors (▲ and ▼). Activation in both assays is expressed as % relative to activation in the presence of rifampicin, 10 μM, in parallel cultures. (b) Liver section from vehicle-dosed rats. (c) Liver section from rats given 4 daily doses of BMS-869780 at 100 mg/kg. A summary of the plasma BMS-869780 exposures from this experiment is shown in Table 5.
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fig10: BMS-869780 caused PXR activation in vitro and lipidosis in rat liver. (a) PXR activation in the presence of BMS-869780 was evaluated in HepG2 cell cultures using a luciferase transcriptional reporter construct (●), or by assay of CYP3A4 mRNA levels in primary human hepatocyte (PHH) cultures from two individual donors (▲ and ▼). Activation in both assays is expressed as % relative to activation in the presence of rifampicin, 10 μM, in parallel cultures. (b) Liver section from vehicle-dosed rats. (c) Liver section from rats given 4 daily doses of BMS-869780 at 100 mg/kg. A summary of the plasma BMS-869780 exposures from this experiment is shown in Table 5.

Mentions: BMS-869780 was evaluated in a range of in vitro off-target activity assays. In one of these assays, pregnane-X-receptor transactivation (PXR-TA), BMS-869780 exhibited robust activity. In further experiments, BMS-869780 was shown to increase CYP3A4 mRNA expression in primary human hepatocytes. In both the PXR-TA and the primary human hepatocytes, transcription was activated at concentrations of 0.3 μM and above (Figure 10(a)), suggesting potential activation of CYP3A4 metabolism and risk for drug-drug interactions in human at the exposures predicted to lower Aβ1-42.


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)

BMS-869780 caused PXR activation in vitro and lipidosis in rat liver. (a) PXR activation in the presence of BMS-869780 was evaluated in HepG2 cell cultures using a luciferase transcriptional reporter construct (●), or by assay of CYP3A4 mRNA levels in primary human hepatocyte (PHH) cultures from two individual donors (▲ and ▼). Activation in both assays is expressed as % relative to activation in the presence of rifampicin, 10 μM, in parallel cultures. (b) Liver section from vehicle-dosed rats. (c) Liver section from rats given 4 daily doses of BMS-869780 at 100 mg/kg. A summary of the plasma BMS-869780 exposures from this experiment is shown in Table 5.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig10: BMS-869780 caused PXR activation in vitro and lipidosis in rat liver. (a) PXR activation in the presence of BMS-869780 was evaluated in HepG2 cell cultures using a luciferase transcriptional reporter construct (●), or by assay of CYP3A4 mRNA levels in primary human hepatocyte (PHH) cultures from two individual donors (▲ and ▼). Activation in both assays is expressed as % relative to activation in the presence of rifampicin, 10 μM, in parallel cultures. (b) Liver section from vehicle-dosed rats. (c) Liver section from rats given 4 daily doses of BMS-869780 at 100 mg/kg. A summary of the plasma BMS-869780 exposures from this experiment is shown in Table 5.
Mentions: BMS-869780 was evaluated in a range of in vitro off-target activity assays. In one of these assays, pregnane-X-receptor transactivation (PXR-TA), BMS-869780 exhibited robust activity. In further experiments, BMS-869780 was shown to increase CYP3A4 mRNA expression in primary human hepatocytes. In both the PXR-TA and the primary human hepatocytes, transcription was activated at concentrations of 0.3 μM and above (Figure 10(a)), suggesting potential activation of CYP3A4 metabolism and risk for drug-drug interactions in human at the exposures predicted to lower Aβ1-42.

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