Pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. Synthesis and SAR of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-pyrrolo[3,4-c]quinoline-1,3-diones.
Synthesis, biological evaluation and structure-activity relationships for a series of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors with IC50 in the range of 3-10 nM have been identified. The most active compound within this series, 7{49} and 7{58}, inhibited caspase-3 with IC50=3 nM.
Kravchenko
Dmitri V
DV
Department of Organic Chemistry, Chemical Diversity Research Institute, Khimki, Moscow Region, Russia. dk@chemdiv.com
Kysil
Volodymyr M
VM
Tkachenko
Sergey E
SE
Maliarchouk
Sergey
S
Okun
Ilya M
IM
Ivachtchenko
Alexandre V
AV
D053148:Caspase 3; D061945:Caspase Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D015363:Quinolones; D053148:Caspase 3