Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino) methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate

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.