Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 10, Pages 7016-7037Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00525
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A series of novel benzamide derivatives were designed and synthesized from the pyridazinone scaffold. Among them, (S)-17b showed potent inhibitory activity against human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line in vitro. Furthermore, (S)-17b demonstrated excellent in vivo antitumor activity in SKM-1 xenograft models, and showed better efficacy on mouse models with intact immune system compared to those with thymus deficiencies. This novel compound (S)-17b may serve as a promising drug candidate for further investigation.
A novel series of benzamide derivatives were successivelydesignedand synthesized prepared from the pyridazinone scaffold. Among them,(S)-17b, demonstrated potent inhibitoryactivity in vitro toward human class I HDAC isoformsand human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellularlevel of acetyl-histone H3 and P21 simultaneously and effectivelyinduced G1 cell cycle arrest and apoptosis. Through oral dosing inSKM-1 xenograft models, (S)-17b exhibitedexcellent in vivo antitumor activity. In addition,compound (S)-17b showed better antitumorefficacy on mouse models with intact immune system than those withthymus deficiencies. Furthermore, this compound displayed a favorablepharmacokinetic profile in ICR mice and SD rat, respectively, minimalmetabolic property differences among hepatocytes from five species,and a low inhibition upon the human ether-a-go-go (hERG) channel withan IC50 value of 34.6 mu M. This novel compound(S)-17b may serve as a new drug candidatefor further investigation.
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