Design and campaign synthesis of pyridine-based histone deacetylase inhibitors.
A lead benzamide, bearing a cyanopyridyl moiety (3), was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Various replacements of the cyano group were explored at the C3-position, along with the exploration of solubility-enhancing groups at the C5-position. It was determined that cyano substitution at the C3-position of the pyridyl core, along with a methylazetidinyl substituent at the C5-position yielded optimal HDAC1 inhibition and anti-proliferative activity in HCT-116 cells.
Andrews
David M
DM
Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. david.andrews@astrazeneca.com
Gibson
Keith M
KM
Graham
Mark A
MA
Matusiak
Zbigniew S
ZS
Roberts
Craig A
CA
Stokes
Elaine S E
ES
Brady
Madeleine C
MC
Chresta
Christine M
CM
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D006655:Histone Deacetylases; C023666:pyridine