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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

An overview of the characterization of BMS-869780 illustrates only the key steps in integration of data. Additional off-target and pharmaceutics evaluations necessary for decisions on individual compounds are not represented in this diagram.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig11: An overview of the characterization of BMS-869780 illustrates only the key steps in integration of data. Additional off-target and pharmaceutics evaluations necessary for decisions on individual compounds are not represented in this diagram.

Mentions: To predict human dose, off-target, and safety margins, the PK/PD relationship determined in rodents was used as a guide, and a target Aβ1-42 ABEC = 25% was chosen, based on evidence from rodent models that 25% might ultimately translate to a significant effect in AD [7]. The assumption that human and rat PK/PD would be similar was supported by the concordance of the human in vitro IC50 with the in vivo IC50s determined in rat and mouse, as discussed above. The human PK parameters were then predicted through allometric scaling of PK in three species; rat, dog, and monkey, using the average bioavailability (F = 28%) achieved with a nanosuspension. The nanosuspension was chosen as a clinically relevant formulation with potential to enhance bioavailability. A dose of 700 mg was calculated to achieve brain Aβ1-42 ABEC = 25%, with associated AUC = 17.6 μM·h and Cmax⁡ = 1.27 μM. These AUC and Cmax⁡ values were then used as benchmarks to compare the Aβ1-42 lowering activity against in vivo side effects and in vitro off-target activities. BMS-869780 did not cause duodenal neoplasia, the characteristic Notch-related side effect observed in rats given GSIs, even after four days dosing that achieved AUC = 316 μM·h and Cmax⁡ = 15.5 μM (Table 5). This predicted a safety margin, specifically related to duodenal toxicity, including Notch-related side effects in rat, of at least 12-fold above the Aβ1-42 lowering exposure benchmarks. On the other hand, lipidosis in the liver was observed after four daily doses of 10 mg/kg with mean Cmax⁡ = 1.9 μM and AUC = 17.5 μM (Table 5), indicating no separation of hepatotoxicity from the Aβ1-42 lowering exposure benchmarks. Subsequent studies with other potent GSMs (not shown) did not exhibit hepatotoxicity under these conditions, suggesting an off-target mechanism of hepatotoxicity. BMS-869780 was evaluated in a wide range of in vitro off-target activity assays. In the case of the human PXR transcriptional reporter assay, BMS-869780 was found to be active at concentrations of 0.3 μM and above. Further experiments confirmed the activation of CYP3A4 transcription in primary human hepatocyte cultures at similar concentrations, raising the possibility of metabolic induction and risk of drug-drug interactions at exposures required for Aβ1-42 lowering in human [79]. An overview of how experimental data were combined to determine off-target and safety margins is shown in Figure 11. In general, many GSMs exhibit poor drug-like properties, in particular high lipophilicity resulting in high active exposures and risk of systemic toxicity. Nevertheless, approaches for further optimization have been proposed, and the potential to improve drug-like properties has been demonstrated [80]. Alternatively, identification of new structural scaffolds might eventually lead to compounds with improved properties. Whether by optimization of current leads or new scaffolds, potentially the most useful guide for future compound design would be the availability of high resolution structures for GSM binding to γ-secretase.


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)

An overview of the characterization of BMS-869780 illustrates only the key steps in integration of data. Additional off-target and pharmaceutics evaluations necessary for decisions on individual compounds are not represented in this diagram.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig11: An overview of the characterization of BMS-869780 illustrates only the key steps in integration of data. Additional off-target and pharmaceutics evaluations necessary for decisions on individual compounds are not represented in this diagram.
Mentions: To predict human dose, off-target, and safety margins, the PK/PD relationship determined in rodents was used as a guide, and a target Aβ1-42 ABEC = 25% was chosen, based on evidence from rodent models that 25% might ultimately translate to a significant effect in AD [7]. The assumption that human and rat PK/PD would be similar was supported by the concordance of the human in vitro IC50 with the in vivo IC50s determined in rat and mouse, as discussed above. The human PK parameters were then predicted through allometric scaling of PK in three species; rat, dog, and monkey, using the average bioavailability (F = 28%) achieved with a nanosuspension. The nanosuspension was chosen as a clinically relevant formulation with potential to enhance bioavailability. A dose of 700 mg was calculated to achieve brain Aβ1-42 ABEC = 25%, with associated AUC = 17.6 μM·h and Cmax⁡ = 1.27 μM. These AUC and Cmax⁡ values were then used as benchmarks to compare the Aβ1-42 lowering activity against in vivo side effects and in vitro off-target activities. BMS-869780 did not cause duodenal neoplasia, the characteristic Notch-related side effect observed in rats given GSIs, even after four days dosing that achieved AUC = 316 μM·h and Cmax⁡ = 15.5 μM (Table 5). This predicted a safety margin, specifically related to duodenal toxicity, including Notch-related side effects in rat, of at least 12-fold above the Aβ1-42 lowering exposure benchmarks. On the other hand, lipidosis in the liver was observed after four daily doses of 10 mg/kg with mean Cmax⁡ = 1.9 μM and AUC = 17.5 μM (Table 5), indicating no separation of hepatotoxicity from the Aβ1-42 lowering exposure benchmarks. Subsequent studies with other potent GSMs (not shown) did not exhibit hepatotoxicity under these conditions, suggesting an off-target mechanism of hepatotoxicity. BMS-869780 was evaluated in a wide range of in vitro off-target activity assays. In the case of the human PXR transcriptional reporter assay, BMS-869780 was found to be active at concentrations of 0.3 μM and above. Further experiments confirmed the activation of CYP3A4 transcription in primary human hepatocyte cultures at similar concentrations, raising the possibility of metabolic induction and risk of drug-drug interactions at exposures required for Aβ1-42 lowering in human [79]. An overview of how experimental data were combined to determine off-target and safety margins is shown in Figure 11. In general, many GSMs exhibit poor drug-like properties, in particular high lipophilicity resulting in high active exposures and risk of systemic toxicity. Nevertheless, approaches for further optimization have been proposed, and the potential to improve drug-like properties has been demonstrated [80]. Alternatively, identification of new structural scaffolds might eventually lead to compounds with improved properties. Whether by optimization of current leads or new scaffolds, potentially the most useful guide for future compound design would be the availability of high resolution structures for GSM binding to γ-secretase.

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