In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform

Newhard, William; Patel, Malini; Cassaday, Jason; Ballard, Jeanine; Squadroni, Brian; Wu, Guoxin; Liu, Jian; Yu, Wei; Kozlowski, Joe; Zuck, Paul; Howell, Bonnie J.; Hazuda, Daria J.; Vargo, Ryan; Barnard, Richard

doi:10.1177/2472555220983810

Cited by 3 publications

(3 citation statements)

References 45 publications

(75 reference statements)

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“…Compounds 31 and 48 have been identified as advanced leads and are being evaluated in safety studies and biological models for HIV latency reactivation. The in vitro target engagement and histone acetylation studies have been published recently . The in vivo histone acetylation studies in rats will be published in due course.…”

Section: Discussionmentioning

confidence: 99%

“…Introduction of a methyl group next to the nitrogen of the quinoline led to 22, which was 3× more potent in the latency reactivation assay than 7. Encouraged by this data, ethyl (23), cyclopropyl (24), methoxy (25), and pyrrolidyl (26) analogues were also prepared. They all showed sub-nM IC 50 's against HDACs 1, 2, 3, and double-digit nM EC 50 's in cellular potency assay.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Novel HDAC inhibitors have been identified with improved enzymatic activity against HDACs 1, 2, and 3, cellular potency in the latency reactivation assay, and minimized serum shift in cellular potency between 0.1 or 5% NHS. Many of these 24 The in vivo histone acetylation studies in rats will be published in due course.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity

Liu

Clausen

et al. 2021

J. Med. Chem.

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We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.

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Section: Discussionmentioning

confidence: 99%