Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPAR?-Targeted Antidiabetics.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a nuclear receptor central to fatty acid and glucose homeostasis. PPAR? is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPAR? with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPAR?, such as INT131 (1), have displayed similar insulin-sensitizing efficacy as TZDs, but lack many side effects. To probe the structure-activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPAR? and identification of moieties of the scaffold 1 key to high transcriptional potency. The sulfonamide linker is critical to activity, substitutions at position 4 of the benzene ring A were associated with higher transcriptional activity, substitutions at position 2 aided in tighter packing and activity, and the ring type and size of ring A affected the degree of activity.

SUBMITTER: Frkic RL 

PROVIDER: S-EPMC5537074 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature