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

A novel series of benzamide derivatives were successively designed and synthesized prepared from the pyridazinone scaffold. Among them, ( S )- 17b , demonstrated potent inhibitory activity in vitro toward human class I HDAC isoforms and human myelodysplastic syndrome (SKM-1) cell line. Also, ( S )- 17b strongly increased the intracellular level of acetyl-histone H3 and P21 simultaneously and effectively induced G1 cell cycle arrest and apoptosis. Through oral dosing in SKM-1 xenograft models, ( S )- 17b exhibited excellent in vivo antitumor activity. In addition, compound ( S )- 17b showed better antitumor efficacy on mouse models with intact immune system than those with thymus deficiencies. Furthermore, this compound displayed a favorable pharmacokinetic profile in ICR mice and SD rat, respectively, minimal metabolic property differences among hepatocytes from five species, and a low inhibition upon the human ether-a-go-go (hERG) channel with an IC 50 value of 34.6 μΜ. This novel compound ( S )- 17b may serve as a new drug candidate for further investigation.