Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.2.1.1 (
ACS
)
78,556
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) and
kuru
in humans, BSE in cattle, and scrapie in sheep. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrP
Sc
) of a normally benign, host cellular protein, denoted PrP
C
. We employed high-throughput screening (HTS) ELISAs to evaluate compounds for their ability to reduce the level of PrP
Sc
in Rocky Mountain Laboratory (RML) prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as
1
,
7
,
13
, and
19
, displayed moderate antiprion activity with EC
50
values in the micromolar range. Key analogs were designed and synthesized based on the SAR, with analogs
41
,
44
,
46
, and
47
found to have sub-micromolar potency. Analogs
41
and
44
were able to penetrate the blood-brain barrier (BBB) and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.
ACS
Med Chem Lett 2013 Apr 11
PMID:Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds. 2384 18
