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.
Penn Center for Molecular Discovery, University of Pennsylvania, 1024 Vagelos Research Laboratories, Philadelphia, PA 19104-6383, USA.
Michael C
MC
Myers
Parag P
PP
Shah
Scott L
SL
Diamond
Donna M
DM
Huryn
Amos B
AB
Smith
D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D015853:Cysteine Proteinase Inhibitors; D006834:Hydrazines; D010069:Oxadiazoles; D013438:Sulfhydryl Compounds; C010877:carbazic acid; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L