5TTO

X-ray crystal structure of PPARgamma in complex with SR1643

Summary for 5TTO

• Entry DOI: 10.2210/pdb5tto/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 4-bromo-N-{3,5-dichloro-4-[(quinolin-3-yl)oxy]phenyl}-2,5-difluorobenzene-1-sulfonamide (3 entities in total)
• Functional Keywords: nuclear receptor, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 63536.86

Authors

Bruning, J.B.,Frkic, R.L.,Griffin, P.,Kamenecka, T.,Abell, A. (deposition date: 2016-11-04, release date: 2017-05-24, Last modification date: 2023-10-04)

Primary citation

Frkic, R.L.,He, Y.,Rodriguez, B.B.,Chang, M.R.,Kuruvilla, D.,Ciesla, A.,Abell, A.D.,Kamenecka, T.M.,Griffin, P.R.,Bruning, J.B.
Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPAR gamma-Targeted Antidiabetics.
J. Med. Chem., 60:4584-4593, 2017

PubMed 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.

PubMed: 28485590
DOI: 10.1021/acs.jmedchem.6b01727

Experimental method

X-RAY DIFFRACTION (2.246 Å)