958772-66-2

Usage

Uses

SID 26681509 is a small molecule cathespin L inhibitor.

Biological Activity

sid 26681509 is a potent and reversible human cathepsin l inhibitor.the cathepsins have been found to comprise a family of lysosomal protease enzymes whose primary functions, such as protein degradation, play a keyl role in normal cellular homeostasis. overexpression of cathepsin l and/or abnormal activity has been implicated in a number of disease states.

in vitro

sid 26681509 was found to inhibit human cathepsin l with an ic50 of 56 nm. after preincubation with enzyme for 1, 2, and 4 h before substrate addition, sid 26681509 showed increasing potency, with ic50 values falling to 7.5, 4.2, and 1.0 nm, respectively, indicating a slow onset of inhibition. sid 26681509 was also observed to be nontoxic to human aortic endothelial cells up to 100 μm. sid 26681509 was active in an in vitro propagation assay against p. falciparum with an ic50 of 15.4 μm. additionally, the thiocarbazate inhibitor was toxic toward l. major promastigotes with an ic50 of 12.5 μm [1].

in vivo

sid 26681509 showed a lack of toxicity to zebrafish in a live organism assay at 100 μm [1].

IC 50

56 nm

references

[1] shah pp,myers mc,beavers mp,purvis je,jing h,grieser hj,sharlow er,napper ad,huryn dm,cooperman bs,smith ab 3rd,diamond sl. kinetic characterization and molecular docking of a novel, potent, and selective slow-binding inhibitor of human cathepsin l. mol pharmacol.2008 jul;74(1):34-41.

Upstream product

• 895854-04-3 2-bromo-N-(2'-ethylphenyl)acetamide 
• 132685-99-5 Boc(L)-tryptophan hydrazide 
• 463-58-1 carbon oxide sulfide 

Downstream Products

• 1007872-55-0 C₂₂H₂₅N₅O₃S 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of a library of thiocarbazates and their activity as cysteine protease inhibitors

Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (-)-11 and (-)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin L in the low nanomolar range.

Design, synthesis, and evaluation of inhibitors of cathepsin L: Exploiting a unique thiocarbazate chemotype

Recently, we identified a thiocarbazate that exhibits potent inhibitory activity against human cathepsin L. Since this structure represents a novel chemotype with potential for activity against the entire cysteine protease family, we designed, synthesized, and assayed a series of analogs to probe the mechanism of action, as well as the structural requirements for cathepsin L activity. Molecular docking studies using coordinates of a papain-inhibitor complex as a model for cathepsin L provided useful insights.