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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

In vitro potency of BMS-869780 in the HTS assay. (a) H4-APPsw cultures were treated overnight with BMS-869780 (a GSM) at a range of concentrations and the relative levels of Aβ1-42 (red ●) and Aβ1-40 (blue ♦) were determined for calculation of IC50 values (summarized in Table 1). (b) H4-APPsw cultures were treated overnight with BMS-299897 (a representative GSI) as described for BMS-869780 in panel (a). IC50 values are summarized in Table 1. (c) IC50 values for Aβ1-42 and Aβ1-40 lowering were determined for 236 GSM (red ●) and for 688 GSI that were mostly of the type containing the aryl sulfonamide core (blue ▲). For some compounds, the Aβ1-40 IC50 value was greater than 30 μM, the highest concentration tested in the Aβ1-40 assay (arrow). (d) The ratio of the Aβ1-40 IC50 to Aβ1-42 IC50 was plotted against Aβ1-42 IC50 for the same 236 GSM illustrated in (c).
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fig2: In vitro potency of BMS-869780 in the HTS assay. (a) H4-APPsw cultures were treated overnight with BMS-869780 (a GSM) at a range of concentrations and the relative levels of Aβ1-42 (red ●) and Aβ1-40 (blue ♦) were determined for calculation of IC50 values (summarized in Table 1). (b) H4-APPsw cultures were treated overnight with BMS-299897 (a representative GSI) as described for BMS-869780 in panel (a). IC50 values are summarized in Table 1. (c) IC50 values for Aβ1-42 and Aβ1-40 lowering were determined for 236 GSM (red ●) and for 688 GSI that were mostly of the type containing the aryl sulfonamide core (blue ▲). For some compounds, the Aβ1-40 IC50 value was greater than 30 μM, the highest concentration tested in the Aβ1-40 assay (arrow). (d) The ratio of the Aβ1-40 IC50 to Aβ1-42 IC50 was plotted against Aβ1-42 IC50 for the same 236 GSM illustrated in (c).

Mentions: While many of the ca. 400 samples showed wide separations between the Aβ1-42 and Aβ1-40 IC50 values, BMS-869780 itself showed only a four-fold separation between the IC50 values (Figure 2(a)), presenting a minimal contrast with GSIs such as BMS-299897 (Figure 2(b)) and BMS-433796 (see summary of IC50 values in Table 1). Nevertheless, as a group, compounds chemically related to BMS-869780 showed limited overlap with GSIs based on the separation of Aβ1-42 and Aβ1-40 IC50 values, as illustrated for 236 GSMs and 688 GSIs (Figure 2(c)). This implies different Aβ-lowering mechanisms between the two groups. The ratios between Aβ1-42 and Aβ1-40 IC50 values in the GSM group ranged from little more than two-fold to almost 250-fold, with a trend toward lower ratios for compounds with lower IC50 values (Figure 2(d)). Anticipating subsequent experiments in the 3xTg mouse, the effect of the presenilin M146V FAD mutant on BMS-869780 potency was evaluated. MEF cell cultures lacking endogenous presenilins were therefore cotransfected with human APP-CTFβ and human presenilin, either wild type or M146V allele. The IC50 for Aβ1-42 was ca. 3-fold higher in cultures expressing the M146V allele, relative to cells expressing wild type presenilin. Likewise, Aβ1-40 IC50 values were ca. 3-fold shifted, although the IC50 appeared lower for Aβ1-40 in the wild type MEF cell cultures than in the H4-APPsw cultures. Thus, BMS-869780 appeared to be a little less potent in the context of the presenilin-1 M146V allele. IC50 values are summarized in Table 1.


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)

In vitro potency of BMS-869780 in the HTS assay. (a) H4-APPsw cultures were treated overnight with BMS-869780 (a GSM) at a range of concentrations and the relative levels of Aβ1-42 (red ●) and Aβ1-40 (blue ♦) were determined for calculation of IC50 values (summarized in Table 1). (b) H4-APPsw cultures were treated overnight with BMS-299897 (a representative GSI) as described for BMS-869780 in panel (a). IC50 values are summarized in Table 1. (c) IC50 values for Aβ1-42 and Aβ1-40 lowering were determined for 236 GSM (red ●) and for 688 GSI that were mostly of the type containing the aryl sulfonamide core (blue ▲). For some compounds, the Aβ1-40 IC50 value was greater than 30 μM, the highest concentration tested in the Aβ1-40 assay (arrow). (d) The ratio of the Aβ1-40 IC50 to Aβ1-42 IC50 was plotted against Aβ1-42 IC50 for the same 236 GSM illustrated in (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4109680&req=5

fig2: In vitro potency of BMS-869780 in the HTS assay. (a) H4-APPsw cultures were treated overnight with BMS-869780 (a GSM) at a range of concentrations and the relative levels of Aβ1-42 (red ●) and Aβ1-40 (blue ♦) were determined for calculation of IC50 values (summarized in Table 1). (b) H4-APPsw cultures were treated overnight with BMS-299897 (a representative GSI) as described for BMS-869780 in panel (a). IC50 values are summarized in Table 1. (c) IC50 values for Aβ1-42 and Aβ1-40 lowering were determined for 236 GSM (red ●) and for 688 GSI that were mostly of the type containing the aryl sulfonamide core (blue ▲). For some compounds, the Aβ1-40 IC50 value was greater than 30 μM, the highest concentration tested in the Aβ1-40 assay (arrow). (d) The ratio of the Aβ1-40 IC50 to Aβ1-42 IC50 was plotted against Aβ1-42 IC50 for the same 236 GSM illustrated in (c).
Mentions: While many of the ca. 400 samples showed wide separations between the Aβ1-42 and Aβ1-40 IC50 values, BMS-869780 itself showed only a four-fold separation between the IC50 values (Figure 2(a)), presenting a minimal contrast with GSIs such as BMS-299897 (Figure 2(b)) and BMS-433796 (see summary of IC50 values in Table 1). Nevertheless, as a group, compounds chemically related to BMS-869780 showed limited overlap with GSIs based on the separation of Aβ1-42 and Aβ1-40 IC50 values, as illustrated for 236 GSMs and 688 GSIs (Figure 2(c)). This implies different Aβ-lowering mechanisms between the two groups. The ratios between Aβ1-42 and Aβ1-40 IC50 values in the GSM group ranged from little more than two-fold to almost 250-fold, with a trend toward lower ratios for compounds with lower IC50 values (Figure 2(d)). Anticipating subsequent experiments in the 3xTg mouse, the effect of the presenilin M146V FAD mutant on BMS-869780 potency was evaluated. MEF cell cultures lacking endogenous presenilins were therefore cotransfected with human APP-CTFβ and human presenilin, either wild type or M146V allele. The IC50 for Aβ1-42 was ca. 3-fold higher in cultures expressing the M146V allele, relative to cells expressing wild type presenilin. Likewise, Aβ1-40 IC50 values were ca. 3-fold shifted, although the IC50 appeared lower for Aβ1-40 in the wild type MEF cell cultures than in the H4-APPsw cultures. Thus, BMS-869780 appeared to be a little less potent in the context of the presenilin-1 M146V allele. IC50 values are summarized in Table 1.

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