Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2).
We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
Heidebrecht
Richard W
RW
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. richard_heidebrecht@merck.com
Chenard
Melissa
M
Close
Joshua
J
Dahlberg
William K
WK
Fleming
Judith
J
Grimm
Jonathan B
JB
Hamill
Julie E
JE
Harsch
Andreas
A
Haines
Brian B
BB
Hughes
Bethany
B
Kral
Astrid M
AM
Middleton
Richard E
RE
Mushti
Chandrasekhar
C
Ozerova
Nicole
N
Szewczak
Alexander A
AA
Wang
Hongmei
H
Wilson
Kevin
K
Witter
David J
DJ
Secrist
J Paul
JP
Miller
Thomas A
TA
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D063065:Organophosphonates; D012097:Repressor Proteins; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases