Synthesis and evaluation of lysine derived sulfamides as histone deacetylase inhibitors.
We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.
Manku
Sukhdev
S
MethylGene Inc., Departments of Medicinal Chemistry, 7220 rue Frederick-Banting, Montreal, Quebec, Canada H4S 2A1.
Allan
Martin
M
Nguyen
Natalie
N
Ajamian
Alain
A
Rodrigue
Jacques
J
Therrien
Eric
E
Wang
James
J
Guo
Tim
T
Rahil
Jubrail
J
Petschner
Andrea J
AJ
Nicolescu
Alina
A
Lefebvre
Sylvain
S
Li
Zuomei
Z
Fournel
Marielle
M
Besterman
Jeffrey M
JM
Déziel
Robert
R
Wahhab
Amal
A
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
D001562:Benzimidazoles; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; C017800:zinc-binding protein; D006655:Histone Deacetylases; D008239:Lysine