PUBLICATION
Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity
- Authors
- Thompson, M.J., Louth, J.C., Ferrara, S., Jackson, M.P., Sorrell, F.J., Cochrane, E.J., Gever, J., Baxendale, S., Silber, B.M., Roehl, H.H., and Chen, B.
- ID
- ZDB-PUB-110713-18
- Date
- 2011
- Source
- European Journal of Medicinal Chemistry 46(9): 4125-32 (Journal)
- Registered Authors
- Baxendale, Sarah, Roehl, Henry
- Keywords
- drug discovery, indoles, prion disease, structure-activity relationships, zebrafish
- MeSH Terms
-
- Animals
- Cell Line
- Drug Discovery
- Indoles/adverse effects
- Indoles/chemistry*
- Indoles/pharmacology*
- Microsomes/drug effects*
- Prions/drug effects*
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 21726921 Full text @ Eur. J. Med. Chem.
Citation
Thompson, M.J., Louth, J.C., Ferrara, S., Jackson, M.P., Sorrell, F.J., Cochrane, E.J., Gever, J., Baxendale, S., Silber, B.M., Roehl, H.H., and Chen, B. (2011) Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity. European Journal of Medicinal Chemistry. 46(9):4125-32.
Abstract
A series of highly potent indole-3-glyoxylamide based antiprion agents was previously characterized, focusing on optimization of structure–activity relationship (SAR) at positions 1–3 of the indole system. New libraries interrogating the SAR at indole C-4 to C-7 now demonstrate that introducing electron-withdrawing substituents at C-6 may improve biological activity by up to an order of magnitude, and additionally confer higher metabolic stability. For the present screening libraries, both the degree of potency and trends in SAR were consistent across two cell line models of prion disease, and the large majority of compounds showed no evidence of toxic effects in zebrafish. The foregoing observations thus make the indole-3-glyoxylamides an attractive lead series for continuing development as potential therapeutic agents against prion disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping