BSecretase Inhibitors

Several inhibitors of b-secretase have been identified in cellular assays but, more often than not, the true nature of the inhibition mechanism was not reported. Broad-spectrum protease inhibitors, for example pepstatin 1, known aspartic protease inhibitors from renin, and HIV protease programs and cocktails thereof, had little inhibitory effect and gave misleading results. But the consequent utilization of the Swedish mutation and structure-activity relationships for an early Bristol-Myers Squibb compound, 2, resulted in OM99-2 (3) and successful co-crystallization with BACE. Activities have been reported for Leu-Ala hydroxy-ethylene isosters such as 4, which provide insight into the mode of binding. These compounds do not really invite drug development, because the obstacles in Alzheimer therapy will be even greater than inhibition of renin and HIV protease. Significant efforts have been made to reduce the molecular weight and the flexibility of the lead structure. The improved binding to the pocket P2' by valine instead of alanines, and the omission of the small interactions of P4 Glu and P4' Phe were first steps taken on a bumpy road. The Elan compounds 5, 6 have lost a good part of their peptide heritage, which is mandatory to obtain sufficient oral absorption and blood-brain barrier penetration.

Despite all the efforts of the pharmaceutical companies and academic groups, non-peptidic lead structures for BACE inhibition are very scarce (Scheme 3.5.5). Takeda reported the tetraline 7, which is not an obvious scaffold for protease inhibition, and therefore likely to originate from high-throughput screening efforts [27]. The activity is poor (IC50 > 1 mM) and the mode of action is uncertain. Lat-ifolin 8, isolated from the heartwood of Dalbergia sissoo, was found to inhibit Ab formation with an IC50 of 180 mM [28].

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