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

ABSTRACT: Fused oxadiazines (3) were discovered as selective and orally bioavailable ?-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 ?-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.

SUBMITTER: Huang X

PROVIDER: S-EPMC4025817 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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

Huang Xianhai X Zhou Wei W Liu Xiaoxiang X Li Hongmei H Sun George G Mandal Mihirbaran M Vicarel Monica M Zhu Xiaohong X Bennett Chad C McCraken Troy T Pissarnitski Dmitri D Zhao Zhiqiang Z Cole David D Gallo Gioconda G Zhu Zhaoning Z Palani Anandan A Aslanian Robert R Clader John J Czarniecki Michael M Greenlee William W Burnett Duane D Cohen-Williams Mary M Hyde Lynn L Song Lixin L Zhang Lili L Chu Inhou I Buevich Alexei A

ACS medicinal chemistry letters 20120904 11

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 eff ...[more]

PMID: 24900409

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Project description:?-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. ?-Secretase cleaves the amyloid precursor proteins (APP) to release A? peptides that likely play a causative role in the pathogenesis of Alzheimer's disease (AD). In addition, ?-secretase cleaves Notch and other type I membrane proteins. ?-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with nondiscriminatory inhibition of Notch signaling, overall APP processing, and other substrate cleavages. Therefore, these findings call for the development of disease-modifying agents that target ?-secretase activity to lower levels of A?42 production without blocking the overall processing of ?-secretase substrates. ?-Secretase modulators (GSMs) originally derived from nonsteroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first-generation GSMs have limited potential because of the low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, ?-secretase, or both. To improve the potency and brain availability, second-generation GSMs, including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes, as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of ?-secretase. In addition, two types of GSMs have distinct binding sites within the ?-secretase complex and exhibit different A? profiles. GSMs induce a conformational change of ?-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.

Project description:INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Dataset Information

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

Publications

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

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