Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer’s disease

Chen, Jian Jeffrey; Qian, Wenyuan; Biswas, Kaustav; Yuan, Chester; Amegadzie, Albert; Liu, Qingyian; Nixey, Thomas; Zhu, Joe Jiang; Ncube, Mqhele; Rzasa, Robert M.; Chavez, Frank; Chen, Ning; DeMorin, Frenel; Rumfelt, Shannon; Tegley, Christopher M.; Allen, Jennifer R.; Hitchcock, Stephen A.; Hungate, Randy; Bartberger, Michael D.; Zalameda, Leeanne; Liu, Yichin; McCarter, John D.; Zhang, Jianhua; Zhu, Li; Babu‐Khan, Safura; Luo, Yi; Bradley, Jodi; Wen, Paul; Reid, Darren L.; Koegler, Frank H.; Dean, Charles R.; Hickman, Dean; Correll, Tiffany L.; Williamson, Toni; Wood, Stephen

doi:10.1016/j.bmcl.2013.09.041

Cited by 16 publications

(7 citation statements)

References 30 publications

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“…Researchers at Amgen carried out high-throughput screening (HTS) for modulators of Aβ42 production in an HEK293 cell line stably expressing guinea pig Swedish mutant SFV-APP695sw. This screen identified oxazole 39 (Figure ) as a novel GSM chemotype . While the imidazole-based GSMs nearly universally require a methoxy group on the aniline for potency, this same methoxy substitution resulted in a loss in potency for this series.…”

Section: Anilinesmentioning

confidence: 99%

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Bursavich¹,

Harrison²,

Blain³

2016

J. Med. Chem.

125

123

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The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain beta amyloid (Aβ) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter non-amyloidogenic Aβ species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as lower cLogP, high central nervous system multiparameter optimization scores, and high sp(3) character.

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Section: Anilinesmentioning

confidence: 99%

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Bursavich¹,

Harrison²,

Blain³

2016

J. Med. Chem.

125

123

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“…As with all olaparib-like molecules, the AZ9482 phthalazinone core mimics the adenine of NAD + and is essential for PARP family binding; this moiety was retained in our AfBP design, along with the central phenyl ring present in all potent compounds in our published series. During the pharmacokinetic optimization of AZ9482 , we demonstrated that altering the pyridine group is tolerated in MPS assays, and while the 3-nitrile is a key backbone hydrogen bond acceptor, the 5-position (Figure A, red star) represents a convenient point from which to build out into a solvent channel with a small photocrosslinkable clickable moiety. , This resulted in probe PARPYnD (Figure A), the synthesis of which is described in the Supplementary Methods section; briefly, commercially available 2-(piperazin-1-yl)pyridine-3-carbonitrile was Boc protected and brominated, and a copper-catalyzed amination was used to install the key aniline group that allowed coupling of the photoaffinity molecule . Boc deprotection and coupling to the phthalazinone core generated AfBP PARPYnD .…”

Section: Results and Discussionmentioning

confidence: 99%

Structure-Guided Design and In-Cell Target Profiling of a Cell-Active Target Engagement Probe for PARP Inhibitors

et al. 2020

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Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to profile PARP engagement in live cells are lacking. Herein, we report the design and application of PARPYnD, the first photoaffinity probe (AfBP) for PARP enzymes based on triple PARP1/2/6 inhibitor AZ9482, which induces multipolar spindle (MPS) formation in breast cancer cells. PARPYnD is a robust tool for profiling PARP1/2 and is used to profile clinical PARP inhibitor olaparib, identifying several novel off-target proteins. Surprisingly, while PARPYnD can enrich recombinant PARP6 spiked into cellular lysates and inhibits PARP6 in cell-free assays, it does not label PARP6 in intact cells. These data highlight an intriguing biomolecular disparity between recombinant and endogenous PARP6. PARPYnD provides a new approach to expand our knowledge of the targets of this class of compounds and the mechanisms of action of PARP inhibitors in cancer.

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“…Most of the reported chiroptical spectral analyses for chiral drugs were accomplished via visual spectral analyses. A table summarizing the chiral drugs whose ACs were investigated [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90] using chiroptical spectroscopic methods are summarized in Table 1. Occasional reviews have also highlighted some of these chiral drugs [42,65,91,92].…”

Section: Chiroptical Spectroscopic Toolsmentioning

confidence: 99%

Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy

Polavarapu

2016

Molecules

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Chiroptical spectroscopy has emerged as a promising tool for the determination of absolute configurations and predominant conformations of chiral molecules in academic laboratories. This promise has led to the adaption of chiroptical spectroscopic methods as valuable tools in chiral drug discovery research programs of the pharmaceutical industry. Most major pharmaceutical companies have invested in in-house chiroptical spectroscopy applications and reported successful outcomes. In the context of continuously increasing applications of chiroptical spectroscopy for chiral molecular structure determination, a review of recent developments and applications for chiral drugs is presented in this manuscript.

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Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer’s disease

Cited by 16 publications

References 30 publications

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Structure-Guided Design and In-Cell Target Profiling of a Cell-Active Target Engagement Probe for PARP Inhibitors

Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy

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