Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease

Abstract

Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure−activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs. KEYWORDS: Alzheimer's disease, oxadiazine, amyloid precursor protein, γ-secreatase modulator, Notch processing, morpholine A lzheimer's disease (AD) is an age-related neurodegenerative disorder that affects millions of elderly people in the United States. It is estimated that more than 35 million people suffer from AD worldwide, with an annual cost of over $600 billion, and the population may increase to more than 115 million by 2050. 1 Because of clear unmet medical need, both academic and industrial laboratories are working very aggressively to develop therapies to halt or even reverse AD. It is believed that the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated protein τ contributes to AD progression. 2−6 Aβ peptide is formed from a larger amyloid precursor protein (APP) via sequential proteolytic cleavage by β-and γ-secretases (Figure 1). 7 γ-Secretase cleaves the APP Cterminal fragment at multiple sites leading to Aβ peptides of 37−42 amino acids of which Aβ 42 , the more hydrophobic form, is the most amyloidogenic and neurotoxic. Although the molecular mechanism of action remains largely unknown, γ-secretase modulators (GSMs) are believed to act at an allosteric site to shift the predominant site of γ-secretase cleavage toward shorter, nonamyloidogenic peptides (e.g., Aβ 38 ) by selectively inhibiting Aβ 42 formation without blocking overall γ-secretase function. This potentially offers a better selectivity window over γ-secretase inhibitors (GSIs) 8−10 versus, for example, notch processing. 11 From an in vitro point of view, the Aβ total /Aβ 42 ratio can be used to distinguish GSMs from GSIs with a ratio of >10 for GSMs and <3 for GSIs. There are two major classes of GSMs in clinical trials: one is the nonsteroidal antiinflammatory acids (NSAIDs), 12,13 and the other is the nonNSAIDs class such as lactam 1 from Eisai. In our effort in the AD area, we have recently identified multiple structural classes 14−18 of GSMs with good in vitro potency and selectivity. Herein, we repo...

4‐Dimethylaminopyridine‐Mediated [3+3] Cycloaddition of Aza‐oxyallyl Cations and Nitrones

“…Nitrogen‐containing heterocycles as key elements are widespread in drug molecules and natural products . As shown in Figure , oxadiazines I as γ‐secretase modulators have been used in the treatment of Alzheimer's disease . 1,2,4‐Oxadiazinan‐2,5‐dione derivatives II are herbicides, diuretics and antiphlogistic pharmaceuticals (Figure ) .…”

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

“…For example, Merck/Schering Plough has reported analogs of E2012, exemplified by GSM-53, that incorporate a conformational constrained fused oxadiazine as an amide replacement. (133, 134) Merck, Hoffman LaRoche, AstraZeneca and Janssen have each disclosed variations of the arylimidazole series that incorporate an aminoheterocycle. For example, Merck replaced the methylenepiperidinone of E2012 with an aminopyridone to give GSM-35.…”

Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease

“…These NSAIDs interact with PS at the luminal side and increase the distance between the N- and C- termini of PS, thus direct the cleavage sites toward Aβ38 instead of Aβ42, without altering total Aβ production ( Lleó et al, 2004 ; Takeo et al, 2014 ). The second generation of GSMs include NSAID-derived carboxylic acid analogs ( Beher et al, 2004 ; Hall et al, 2010 ) and non-NSAID GSMs ( Huang et al, 2012 ; Sun et al, 2012 ). The second-generation GSMs have better pharmacokinetic properties, and several of them entered clinical trials, including CHF 5074, EVP-0962, and PF-06648671 ( Table 2 ).…”