Premium
Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease
Author(s) -
Thompson Mark J.,
Louth Jennifer C.,
Ferrara Steven,
Sorrell Fiona J.,
Irving Benjamin J.,
Cochrane Edward J.,
Meijer Anthony J. H. M.,
Chen Beining
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000383
Subject(s) - indole test , moiety , lead compound , in vivo , scrapie , heteroatom , in vitro , stereochemistry , chemistry , structure–activity relationship , biology , disease , computational biology , pharmacology , combinatorial chemistry , biochemistry , medicine , prion protein , genetics , pathology , organic chemistry , ring (chemistry)
Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC 50 <10 n M ). After examining a range of substituents at the para ‐position of the N ‐phenylglyoxylamide moiety, five‐membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie‐infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole‐3‐glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.