A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety.
Herein, we examine the potential of a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of caspase 1 (IC(50) values < or =1 nM). Examination of these novel small molecules against a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition over other caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings, including in vivo analyses.
National Institutes of Health, National Human Genome Research Institute, NIH Chemical Genomics Center, Rockville, Maryland 20850, USA.
Matthew B
MB
Boxer
Amy M
AM
Quinn
Min
M
Shen
Ajit
A
Jadhav
William
W
Leister
Anton
A
Simeonov
Douglas S
DS
Auld
Craig J
CJ
Thomas
D010129:4-Aminobenzoic Acid / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D020134:Catalytic Domain; D003198:Computer Simulation; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004151:Dipeptides / Q000737:chemistry; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D011422:Propionates; D062366:para-Aminobenzoates; C520022:belnacasan; D020170:Caspase 1; C029658:propionic acid; D010129:4-Aminobenzoic Acid