The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors.
This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.
Hamblett
Christopher L
CL
Department of Drug Design and Optimization-Medicinal Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. christopher-hamblett@merck.com
Methot
Joey L
JL
Mampreian
Dawn M
DM
Sloman
David L
DL
Stanton
Matthew G
MG
Kral
Astrid M
AM
Fleming
Judith C
JC
Cruz
Jonathan C
JC
Chenard
Melissa
M
Ozerova
Nicole
N
Hitz
Anna M
AM
Wang
Hongmei
H
Deshmukh
Sujal V
SV
Nazef
Naim
N
Harsch
Andreas
A
Hughes
Bethany
B
Dahlberg
William K
WK
Szewczak
Alex A
AA
Middleton
Richard E
RE
Mosley
Ralph T
RT
Secrist
J Paul
JP
Miller
Thomas A
TA
D015120:6-Aminonicotinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000737:chemistry; D001682:Biological Availability; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D015120:6-Aminonicotinamide