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