1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads

Publication: J Med Chem
Software: ADMET Predictor®


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia in the elderly. According to the World Health Organization (WHO), dementia affects 47.5 million people worldwide, a number that is projected to triple by 2050 with the aging population.1,2 AD is characterized by progressive deposition of amyloid and misfolded Tau, followed by neurodegeneration and loss of function, leading ultimately to death.3 Of the many attempts to target the underlying pathogenesis, amyloid lowering approaches have made the most progress so far, albeit without delivering a therapy to date.4 Amyloid oligomer and plaque formation is thought to occur when the balance between nonamyloidogenic (α-secretase mediated) and the amyloidogenic processing of amyloid precursor protein (APP) is shifted (familial AD) or clearance of amyloid is impaired (sporadic AD).5,6 In the amyloidogenic pathway, β-secretase 1 (BACE1) cleaves APP, producing a 99 amino acid length soluble peptide fragment called C99, which is the rate-limiting step in Aβ formation. This peptide is further processed by γ-secretase to 36−43 amino acid length Aβ species, of which the longer isoforms, especially Aβ42, are the most fibrillogenic and neurotoxic.7 Consequently, both βsecretase and γ-secretase are being pursued as targets to modulate Aβ production.8 Since its discovery in 1999,9 BACE1 has been a highly challenging target for drug discovery, and only after years of research medicinal chemists have managed progressing small molecule BACE1 inhibitors in clinical trials.10
A breakthrough in the development of nonpeptidomimetic BACE1 inhibitors was the identification of amidine- and guanidine-containing small molecules. Compared to previous peptidomimetic and amino-alcohol derived inhibitors, these molecules form a salt bridge and hydrogen bond interactions with Asp32 and Asp228 in the catalytic site of BACE1 in an optimal way (see schematic in Chart 1).11 The use of a quaternary center alpha to the amidine or guanidine function permits substituents to enter adjacent binding pockets such as S2′, S1, and S3.12 The S3 pocket can be efficiently targeted via amide-tethered biaryl systems (Chart 1). In these amidine
prototypes, the central aromatic ring (A) is a direct substituent on the quaternary center. The A-ring and amide nitrogen occupy the S1 pocket, whereas the distal aromatic ring (B) extends into the S3 pocket. The B-ring is generally a 2-pyridyl or 2-pyrazinyl ring, allowing for a quasicoplanar orientation with the A-ring.