Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside

Fuller, Nathan O.; Hubbs, Jed L.; Austin, W. F.; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn; Tate, Barbara; Xia, Weiming; Ives, Jeffrey L.; Findeis, Mark A.; Bronk, Brian S.

doi:10.1021/ml300256p

Cited by 22 publications

(12 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings that CA and other steroids can modify Aβ production expand the growing number of studies that demonstrate how cholesterol and other steroids can modulate Aβ profiles [ 47 – 54 ]. Of particular interest are studies showing that cholesterol binds to APP CTFβ [ 22 , 23 ], albeit with low affinity, as this might suggest that CA, a cholesterol metabolite, could also interact with CTFβ.…”

Section: Discussionsupporting

confidence: 65%

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator

Jung

Price

Ladd

et al. 2015

Mol Neurodegeneration

View full text Add to dashboard Cite

BackgroundAmyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer’s disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1−/−) and Cyp7b1 knockout (Cyp7b1−/−) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1−/− had increased brain Aβ42, whereas Cyp7b1−/− mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0021-z) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 65%

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator

Jung

Price

Ladd

et al. 2015

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…In another approach to modifying the natural product 1 to elaborate on SAR and generate new potent compounds no longer containing the large and polar glycoside, the ability to directly modify the sugar was exploited ( Figure 5 ) [ 24 ]. Selective 1,2-diol-directed oxidation of the sugar in 6 affords the dialdehyde 14 .…”

Section: Novel Gamma Secretase Modulators Based On Black Cohoshmentioning

confidence: 99%

“…cLogP remained high at 4.5. Having established practical access to morpholine derivatives, it was possible to prepare an extensive SAR series of compounds which produced a diverse range of potent and selective compounds including morpholines modified with sulfonamide, urea and amide groups [ 24 ].…”

Section: Novel Gamma Secretase Modulators Based On Black Cohoshmentioning

confidence: 99%

Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

Findeis¹,

Schroeder

Creaser³

et al. 2015

Medicines

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease is characterized by pathogenic oligomerization, aggregation, and deposition of amyloid beta peptide (Aβ), resulting in severe neuronal toxicity and associated cognitive dysfunction. In particular, increases in the absolute or relative level of the major long form of Aβ, Aβ42, are associated with increased cellular toxicity and rapidity of disease progression. As a result of this observation, screening to identify potential drugs to reduce the level of Aβ42 have been undertaken by way of modulating the proteolytic activity of the gamma secretase complex without compromising its action on other essential substrates such as Notch. In this review we summarize results from a program that sought to develop such gamma secretase modulators based on novel natural products identified in the extract of Actaea racemosa, the well-known botanical black cohosh. Following isolation of compound 1 (SPI-014), an extensive medicinal chemistry effort was undertaken to define the SAR of 1 and related semisynthetic compounds. Major metabolic and physicochemical liabilities in 1 were overcome including replacement of both the sugar and acetate moieties with more stable alternatives that improved drug-like properties and resulted in development candidate 25 (SPI-1865). Unanticipated off-target adrenal toxicity, however, precluded advancement of this series of compounds into clinical development.

show abstract

“…2−4 Semisynthetic derivatives featuring a C3 morpholine acetal and a C24 ether on the modified triterpene scaffold emerged as particularly potent GSMs. 2,3 Further refinement of the series led to the discovery of SPI-1865 (1), which was ultimately selected as a candidate for further development. 5 In order to provide 1 in the quantities required for our preclinical and early clinical development efforts, significant improvements to the synthetic route were required to enhance the overall efficiency and throughput.…”

Section: ■ Introductionmentioning

confidence: 99%

Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator

Fuller¹,

Hubbs²,

Austin³

et al. 2014

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plantsterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compound was the development of a four-reaction telescope process and a selective O-alkylation of a triol intermediate. These improvements enabled the successful delivery of kilogram-scale batches of API for preclinical development studies. ■ INTRODUCTIONDuring the course of research efforts focused on developing a γ-secretase modulator (GSM) as a potential treatment for Alzheimer's disease (AD), we discovered a new structural class of GSMs. 1 A recent series of publications documents our early work on this series of molecules, which is derived from a complex plant triterpene found in black cohosh (Actaea racemosa). 2−4 Semisynthetic derivatives featuring a C3 morpholine acetal and a C24 ether on the modified triterpene scaffold emerged as particularly potent GSMs. 2,3 Further refinement of the series led to the discovery of SPI-1865 (1), which was ultimately selected as a candidate for further development. 5 In order to provide 1 in the quantities required for our preclinical and early clinical development efforts, significant improvements to the synthetic route were required to enhance the overall efficiency and throughput. In this publication, we discuss the synthetic challenges associated with the synthesis of 1 and describe how we were able to develop a multireaction telescope sequence and selective O-alkylation conditions that allowed us to execute the kilogram-scale synthesis of the target compound. ■ RESULTS AND DISCUSSIONFirst-Generation Synthesis. The initial medicinal chemistry route to 1, designed to install a variety of substituents on the azetidine nitrogen, utilized our natural-product-derived starting material 2 obtained from the crude root extract of black cohosh. 6 The synthesis commenced with a double oxidative cleavage of C3 terpene glycosides 2 (Scheme 1). 7,8 The resulting dialdehyde could be used without purification in the subsequent double reductive amination with 1-Boc-3-aminoazetidine hydrochloride to provide N-Boc-azetidinylmorpholine 3. Reduction of the C15 ketone proceeded with high diastereoselectivity (>95:5 dr) to give the C15 alcohol, and purification provided 4 in 61% yield over three steps when corrected for the purity of starting material 2. 9 In order to avoid any potential problems with the selectivity of a downstream Oalkylation, the C15 hydroxyl group was protected as the triethylsilyl ether prior to hydrolysis of the C24 acetate to unveil the C24,C25 diol 5. We found that we could selectively alkylate the C24 hydroxyl over the tertiary C25 hydroxyl to provide C24 ethyl ether 6 (73% yield over two steps). Finally, the synthesis of the target compound was completed by employing a two-step process involving initial double deprotection of the N-Boc-carbamate and the C15 triethylsilyl ether under acidic conditions followed by reductive amination with aceton...

show abstract

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside

Cited by 22 publications

References 37 publications

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator

Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator

Contact Info

Product

Resources

About