Optimization of a series of potent and selective ketone histone deacetylase inhibitors.
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK.
Pescatore
Giovanna
G
IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy. giovanna_pescatore@merck.com
Kinzel
Olaf
O
Attenni
Barbara
B
Cecchetti
Ottavia
O
Fiore
Fabrizio
F
Fonsi
Massimiliano
M
Rowley
Michael
M
Schultz-Fademrecht
Carsten
C
Serafini
Sergio
S
Steinkühler
Christian
C
Jones
Philip
P
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry*; D008956:Models, Chemical; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007659:Ketones; D011994:Recombinant Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D015032:Zinc