Optimization of a Natural Product-Based Class of γ-Secretase Modulators

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

doi:10.1021/jm300976b

Cited by 43 publications

(29 citation statements)

References 19 publications

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“…Inclusion of the basic morpholine was expected to assist in permeating the blood-brain barrier as well, in comparison with other compounds in this series. Preliminary pharmacokinetic studies in normal CD1 mice demonstrated sufficient CNS availability to allow study of PK/PD responses in vivo [25]. While having an improved profile in comparison with the native glycoside, these morpholine series compounds still required further optimization to achieve a more robust drugability profile.…”

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

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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.

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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

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“…High-performance liquid chromatography (HPLC) was performed on a Gilson system utilizing a Gilson GX-271 liquid handler, a Gilson 322 H2 dual solvent pump, a Gilson Prep ELS-II detector, and a Luna C18 column (50 mm × 21.20 mm, 5 μm). Unless stated otherwise, the mobile phase was CH 3 . The reaction mixture was cooled to room temperature and then concentrated under reduced pressure (50 mbar, 35°C) to remove THF.…”

Section: ■ Experimental Detailsmentioning

confidence: 99%

“…MS , and the mixture was stirred for 10 min and then concentrated under reduced pressure to provide the amine hydrochloride salt as a white powder. To the amine salt was added a solution of crude dialdehyde 2a in 9:1 EtOH/AcOH (500 mL) followed by NaBH(OAc) 3 (48.10 g, 226.3 mmol). The reaction mixture was stirred at RT for 90 min and then transferred to a mixture of CH 2 Cl 2 (1 L) and H 2 O (1 L), and the layers were separated.…”

Section: ■ Experimental Detailsmentioning

confidence: 99%

“…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%

“…Since neither starting material 4a or product 5 ionize well by LC−MS, aliquots were removed, diluted with CH 2 Cl 2 , and treated with a drop of concentrated HCl to cleave the silyl ether. The reaction progress was measured by the disappearance of 4a minus SiEt3 (MS (ESI+): m/z = 773 [M + H] + ) and the appearance of 5 minus SiEt 3 (MS (ESI+): m/z = 731 [M + H] + )…”

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confidence: 99%

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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.

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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...

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Metal–Organic Framework Based on Copper and Carboxylate‐Imidazole as Robust and Effective Catalyst in the Oxidative Amidation of Carboxylic Acids and Formamides

Albert‐Soriano

Pastor

2016

Eur J Org Chem

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A metal-organic framework (MOF) based on copper and 1,3-bis(carboxymethyl)imidazole [Cu(bcmim)2] has been prepared up to gram-scale, using a precipitation methodology at room temperature. The MOF-Cu(bcmim)2 has proved to be a very efficient catalyst in the preparation of amides via an oxidative coupling between carboxylic acids and formamides in the presence of an oxidant, such as TBHP. The methodology for the preparation of amides has shown to be very robust regardless of the carboxylic acid, giving good conversions and selectivities. The heterogeneous catalyst has been recovered unaltered after the reaction, being easily separated from the reaction mixture and subsequently reactivated by suitable treatment. Moreover, the coupling reaction has been scaled up to gram-scale, being possible to prepare valuable products, such as fatty acid amides (i.e. 1-palmitoylpiperidine).

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Optimization of a Natural Product-Based Class of γ-Secretase Modulators

Cited by 43 publications

References 19 publications

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

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

Metal–Organic Framework Based on Copper and Carboxylate‐Imidazole as Robust and Effective Catalyst in the Oxidative Amidation of Carboxylic Acids and Formamides

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