In:
QSAR & Combinatorial Science, Wiley, Vol. 28, No. 5 ( 2009-05), p. 576-586
Abstract:
Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that α‐alkyl substitution leads to balanced low micromolar‐active dual agonists of PPARα and PPARγ. Taking α‐hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3‐dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPARγ activity but further increased PPARα activity leading to nanomolar activities. Supporting docking studies proposed that the ( R )‐enantiomer should fit the PPARα ligand‐binding pocket better and thus be more active than the ( S )‐enantiomer. Single enantiomers of selected active analogues were then prepared by enantio‐selective synthesis and enantio‐selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.
Type of Medium:
Online Resource
ISSN:
1611-020X
,
1611-0218
DOI:
10.1002/qsar.200860163
Language:
English
Publisher:
Wiley
Publication Date:
2009
detail.hit.zdb_id:
2537668-8
detail.hit.zdb_id:
2010584-8
SSG:
12
SSG:
15,3
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