BACE Inhibitors

Abstract

Inhibition of BACE1 has emerged as a leading approach to the development of disease-modifying treatments for Alzheimer's disease (AD). Fragment-based drug discovery (FBDD) methods have played a major role in the discovery of novel, ligand-efficient BACE1 inhibitor chemotypes that subsequently have been optimized to have desirable pharmacokinetics (PK) and brain penetration with excellent ancillary profiles. Key components to the success of FBDD approaches targeting BACE1 were (i) identification of various amidine-containing fragments in which the amidine engaged in a network of hydrogen bond donor–acceptor interactions with the BACE1 catalytic dyad, (ii) design and/or identification of nonplanar cyclic amidine scaffolds, and (iii) structure and medicinal chemistry knowledge-based optimization with an emphasis on ligand efficiency. While a number of other fragments and scaffolds in addition to the amidines were identified through screening (e.g., primary amines and aminopyridines, among others), these have met with less success in producing advanced BACE1 inhibitors. This chapter will focus primarily on the role of fragment-based approaches to the discovery of the nonplanar cyclic amidine class of BACE1 inhibitors that have produced the most advanced inhibitors currently in clinical development as potential disease-modifying treatments for AD. Beyond the peptidomimetics, it has proven challenging to develop nonpeptidic “second-generation” BACE1 inhibitors that exhibit brain Ap lowering with a dose and safety profile suitable for clinical progression. Fragment-based approaches have provided novel and structurally diverse chemotypes that, together with extensive SAR exploration using in vitro and in vivo model systems, have afforded a wealth of structure- and property-based knowledge over the past decade, significantly advancing our understanding of what makes a “good” BACE inhibitor. This chapter discusses the major role FBDD played in the development of such chemotypes, including the nonplanar cyclic amidines, a chemotype that ultimately enabled researchers to develop selective BACE inhibitors that are more drug-like in terms of MW, ClogP, and PSA, that have lower susceptibility to P-gp efflux, and most importantly that penetrate the CNS and effectively reduce Ap levels, some of which progressed into clinical development.