Using difluoroketone peptidomimetics previously shown to reversibly inhibit γ-secretase activity in CHO cells, Michael Wolfe reported that increasing the bulkiness of the P1 substituent of these compounds increased their potency, thus, suggesting that γ-secretase has a large S1 pocket (122.3). Moreover, analysis of the effects of these compounds on Aβ40 and Aβ42 secretion indicated that the activity responsible for Aβ40 production is more susceptible to inhibition than the activity responsible for Aβ42 generation. Intriguingly, at low inhibitor concentrations the amount of Aβ42 in conditioned media was actually increased. Wolfe also found that Aβ42 production was selectively increased after removal of reversible γ-secretase inhibitors and he cautioned that inappropriate pharmacokinetic profiles for drugs that work at this level may ironically lead to the opposite of the therapeutic goal, which is to lower Aβ42. These data suggest either that A-beta40 and Aβ42 are produced by discrete enzymes or that they are produced by the same enzyme with two distinct pharmacological activities. Wolfe favors the latter and is currently undertaking studies using irreversible bromoacetyl difluoroalcohols inhibitors to definitively identify the γ-secretase activities responsible for Aβ40 and Aβ42 production.—Dominic Walsh


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