Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization.
The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
Kattar
Solomon D
SD
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. sam_kattar@merck.com
Surdi
Laura M
LM
Zabierek
Anna
A
Methot
Joey L
JL
Middleton
Richard E
RE
Hughes
Bethany
B
Szewczak
Alexander A
AA
Dahlberg
William K
WK
Kral
Astrid M
AM
Ozerova
Nicole
N
Fleming
Judith C
JC
Wang
Hongmei
H
Secrist
Paul
P
Harsch
Andreas
A
Hamill
Julie E
JE
Cruz
Jonathan C
JC
Kenific
Candia M
CM
Chenard
Melissa
M
Miller
Thomas A
TA
Berk
Scott C
SC
Tempest
Paul
P
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D015195:Drug Design; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C110550:HDAC1 protein, human; C533426:Hdac2 protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2