Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles selective for the HDAC6 isoform

Blackburn, Christopher; Barrett, Cynthia; Brunson, Mable; Chin, Janice E.; England, Dylan B.; Garcia, Kris; Gigstad, Kenneth M.; Gould, Alexandra E.; Gutierrez, Juan A.; Hoar, Kara M.; Rowland, R. Scott; Tsu, Christopher; Ringeling, John; Wager, Krista; Xu, He N.

doi:10.1016/j.bmcl.2014.10.022

Cited by 16 publications

(17 citation statements)

References 33 publications

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“…In further modications, this group designed three additional series based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, 4,5,6,7-tetrahydropyrazolopyrazine and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazines. 133 And 63 was the most potent HDAC6 inhibitors in these series of compounds, with IC 50 value of 33 nM, almost 100-fold selectivity versus HDAC8. Homology modeling revealed that fused ring spacer was more effectively occupied the channel of HDAC6, and the hydrophobic capping group interacted with the protein surface (Fig.…”

Section: Class II Selective Hdacismentioning

confidence: 94%

Next-generation of selective histone deacetylase inhibitors

Yang

Zhao

et al. 2019

RSC Adv.

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Section: Class II Selective Hdacismentioning

confidence: 94%

Next-generation of selective histone deacetylase inhibitors

Yang

Zhao

et al. 2019

RSC Adv.

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“…Compound 29 was prepared by employing a similar procedure to that for compound 15 , with 3-methylfuran-2-carboxylic acid and ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate ( 28 ) 26,32 . It was obtained as a white solid in 65% yield.…”

Section: Methodsmentioning

confidence: 99%

Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex

et al. 2017

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Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into are combinant RSV virus and applied the strain to high-throughput screening. Counter screening of candidates returned 14 confirmed hits with activity in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50=0.21 µM, selectivity index (SI) 40), and scaffold. Resynthesis confirmed potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogs (i.e. 8n: EC50=0.06 µM, SI 500) that establish a platform for the development of a therapeutic candidate.

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“…The unique selectivity may because HDAC6 has a wider catalytic channel compared with other HDACs, allowing for the recruitment of bulkier linker elements. A follow-up study showed that by replacing the phenyl ring by pyrrole, the binding affinity of analog 39 slightly increased [100].…”

Section: Aromatic Hydroxamic Acid-derived Inhibitorsmentioning

confidence: 99%

Recent advances in small molecular modulators targeting histone deacetylase 6

Xiao

Zhang

2020

Future Drug Discovery

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Histone deacetylase 6 (HDAC6) is a unique isozyme in the HDAC family with various distinguished characters. HDAC6 is predominantly localized in the cytoplasm and has several specific nonhistone substrates, such as α-tubulin, cortactin, Hsp90, tau and peroxiredoxins. Accumulating evidence reveals that targeting HDAC6 may serve as a promising therapeutic strategy for the treatment of cancers, neurological disorders and immune diseases, making the development of HDAC6 inhibitors particularly attractive. Recently, multitarget drug design and proteolysis targeting chimera technology have also been applied in the discovery of novel small molecular modulators targeting HDAC6. In this review, we briefly describe the structural features and biological functions of HDAC6 and discuss the recent advances in HDAC6 modulators, including selective inhibitors, chimeric inhibitors and proteolysis targeting chimeras for multiple therapeutic purposes.

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Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles selective for the HDAC6 isoform

Cited by 16 publications

References 33 publications

Next-generation of selective histone deacetylase inhibitors

Next-generation of selective histone deacetylase inhibitors

Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex

Recent advances in small molecular modulators targeting histone deacetylase 6

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