Discovery of indole tetrafluorophenoxymethylketone-based potent novel small molecule inhibitors of caspase-3

• Published in: Organic and medicinal chemistry letters Vol. 2; no. 1; p. 27
• Main Authors: Samiulla, Dodheri Syed, Naidu, Andra, Rao, Gummadi Venkateshwar, Ramachandra, Murali
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 16-07-2012; Springer Nature B.V; BioMed Central Ltd; Springer
• Subjects: Chemistry; Chemistry and Materials Science; Medicinal Chemistry; Organic Chemistry; Original; Original Article; Small molecule; Inhibition; Caspase-3; Apoptosis
• ISSN: 2191-2858; 2191-2858
• DOI: 10.1186/2191-2858-2-27

Background
Caspase-3 inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death. Interest in caspase-3 as a therapeutic target has led many to pursue the development of inhibitors. To date, only a few series of non-peptide inhibitors have been described, and these have limitations on their drug-like properties.
Methods
Here, we report the screening of 70 novel small molecules against the caspase-3 enzyme which belongs to four different series (indole fluoromethylketone, indole difluoro and tetrafluorophenoxymethylketone, and oxalamide). Selected molecules were subjected for counter-screening, cell-based, ADME/PK assays in order to understand the potency and drug-like properties.
Results
The screening yielded series of hits with IC
50
values ranging from 0.11 to 10 μM with reasonable SAR, irreversible mode of inhibition, and reasonable selectivity against other proteases including caspase-1, cathepsin B and D, and thrombin. On the basis of
in vitro
profile, the selected molecules were evaluated for their drug-like properties. Among the compounds evaluated, compound
3D
exhibited good solubility, low permeability, interaction with efflux pump, and low potential for CYP450 drug-drug interaction. After intravenous administration, compound
3D
showed low clearance (588 ml/hr/kg), medium volume of distribution, and good oral bioavailability (90%).
Conclusions
These results support further advancement of compound
3D
in different apoptotic models to develop as a new anti-apoptotic agent in relevant disease conditions.