Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease

Huang, Hongbing; La, Daniel S.; Cheng, Alan C.; Whittington, Douglas A.; Patel, Vinod F.; Chen, Kui; Dineen, Thomas A.; Epstein, Oleg; Graceffa, Russell F.; Hickman, Dean; Kiang, Y.‐H.; Louie, Steven W.; Luo, Yi; Wahl, R.; Wen, Paul; Wood, Stephen; Fremeau, Robert T.

doi:10.1021/jm300598e

Cited by 64 publications

(54 citation statements)

References 71 publications

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“…Moreover, mild hyperthermia was found to inhibit HRR and to sensitize cells to PARP-inhibitors (Krawczyk et al, 2011; Bergs et al, 2013). In addition specific inhibitors of HRR are now being identified in specialized screens, like BO2, which inhibits the RAD51 activity in strand exchange (Huang et al, 2012) and RI-1, a specific inhibitor of RAD51 that covalently binds to RAD51 and suppresses RAD51 nucleoprotein filament formation (Budke et al, 2012). …”

Section: Radiosensitization By Chemotherapeutic Agents Through Inhibimentioning

confidence: 99%

DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

Mladenov¹,

Magin²,

Soni³

et al. 2013

Front. Oncol.

234

193

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Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress – a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.

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Section: Radiosensitization By Chemotherapeutic Agents Through Inhibimentioning

confidence: 99%

DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

Mladenov¹,

Magin²,

Soni³

et al. 2013

Front. Oncol.

234

193

View full text Add to dashboard Cite

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“…16 Previously, we reported the discovery of potent aminooxazoline xanthene BACE1 inhibitors rationally designed using a structure-and property-based approach. 12 In the course of lead optimization, compound 1 was identified as a potent BACE1 inhibitor. 17 Compound 1 acutely lowered CSF and brain Aβ40 by approximately 80% and 61%, respectively, 4 h postdose when administered orally to rats at 30 mg/kg.…”

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confidence: 99%

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

Cheng

Brown

Judd

et al. 2015

ACS Med. Chem. Lett.

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BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a diseasemodifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure-and propertybased approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model. KEYWORDS: β-site amyloid precursor protein cleaving enzyme 1 (BACE1), Alzheimer's disease (AD), Aβ, aminooxazoline, xanthene A lzheimer's disease (AD) is the most common neurodegenerative disorder and accounts for 50−80% of dementia cases identified each year. Current therapeutics for AD only provide temporary symptomatic relief and do not address the underlying neuropathology. A therapeutic treatment that directly modifies the progression of the disease remains one of the largest unmet medical needs in neurobiology.The most widely held hypothesis for the underlying pathogenesis of AD posits that aggregation of β-amyloid peptides (Aβ) and deposition into amyloid plaques in the neural parenchyma play an essential role. Aβ is produced by sequential endoproteolytic cleavage of amyloid precursor protein (APP) by the aspartyl protease β-site APP cleaving enzyme-1 (BACE1) and γ-secretase.

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“…[9] Then, trixanthone was synthesized through an intramolecular electrophilic aromatic substitution reaction of compound 4 b in concentrated H 2 SO 4 at 80 8C. [10] The overall yield for the three-step synthesis was 71 % and compound 4 could be obtained on a multi-gram scale, thus indicating that this approach was quite practical. The overall yields for the three-step syntheses of compounds 1-3 were 83 %, 95 %, and 63 %, respectively.…”

Section: Synthesismentioning

confidence: 99%

Synthesis of Di‐ and Trixanthones that Display High Stability and a Visual Fluorescence Response to Strong Acid

Wang

Shao

et al. 2014

Chemistry An Asian Journal

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Three dixanthones (1-3) and an unprecedented C(3h)-symmetric trixanthone (4) were synthesized through a three-step approach in overall yields above 63%. These compounds possessed a planar π-conjugated system and formed tight face-to-face columnar stacks, as confirmed by single-crystal structural analysis. In comparison with xanthone, the fluorescence emissions of compounds 1-4 showed significant red-shifts, with improved quantum yields. Moreover, the fluorescence emissions of compounds 1-4 could be modulated in a strongly acidic environment without decomposition, which led to a further red-shift of the emissions, as well as enhancement of the emission intensities. These compounds have potential applications as optoelectronic materials and/or chemosensors.

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Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease

Cited by 64 publications

References 71 publications

DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

Synthesis of Di‐ and Trixanthones that Display High Stability and a Visual Fluorescence Response to Strong Acid

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