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

Abstract：

:Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPARγ, 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 PPARγ 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Frkic RL,He Y,Rodriguez BB,Chang MR,Kuruvilla D,Ciesla A,Abell AD,Kamenecka TM,Griffin PR,Bruning JB

doi

10.1021/acs.jmedchem.6b01727

subject

Has Abstract

pub_date

2017-06-08 00:00:00

pages

4584-4593

issue

11

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

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