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. 2017 Jun 8;60(11):4584-4593.
doi: 10.1021/acs.jmedchem.6b01727. Epub 2017 May 22.

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

Affiliations

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

Rebecca L Frkic et al. J Med Chem. .

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.

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Conflict of interest statement

Notes: The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical composition of partial agonist 1. The compound is comprised of three major moieties, denoted A, B, and C. The potential substitution positions on ring A are numbered.
Figure 2
Figure 2
Crystal structure of 10 bound to PPARγ LBD. (A) Ribbons diagram of the PPARγ LBD (green) in complex with 10 (blue sticks). (B) Comparison of 10 (blue sticks) binding mode to 1 (yellow sticks), with the main scaffold in the same position and some similar hydrogen bonds formed (1; PBD: 3FUR). (C) Superimposition of 10 and 1 in the region contacting the β-sheet and H3.
Figure 3
Figure 3
Superimposition of docked 1 analogs. The ligands (colored sticks) that have been shown to bind to PPARγ were docked in silico to the PPARγ LBD receptor (blue ribbons). The scaffold of the ligands binds in a similar position, with slight variations at ring A due to substitutions at that location.
Figure 4
Figure 4
Substitution of a sulfonamide for an amide linker has detrimental effects on the capability of 7 to bind to PPARγ. Shown is a superimposition of the 7 structure (white) with the 1 structure (green). The carbon of the C=O in 7 (white sticks) is confined to a planar conformation which prevents the A ring of 7 from making favorable π–π interactions with Phe363 as well as hydrophobic interactions with residues of the binding pocket.
Figure 5
Figure 5
Superimposition of ligands (colored sticks) containing a 4-Br substitution in benzene ring A reveal very similar positions of the bromine atom within the binding pocket of PPARγ (green ribbons). A bromine at position 4 of ring A results in higher affinity of the ligand. The presence of a Br atom in this position enables a weak hydrogen bond with the backbone nitrogen of Phe282 (shown as dashes).
Figure 6
Figure 6
Effective space filling within the PPARγ LBD binding pocket has been shown to correlate with higher affinities. Displayed are superimpositions of the compound 1 analogs (colored sticks) bound to PPARγ (ribbons, green or blue), and a surface representation of the ligand binding pocket (gray surface). Ligands with substitutions at (A) position 2 of ring A have better packing within the pocket and higher affinities than (B) those which have substitutions at other positions. Ligands with substitutions at position 2 include 3 (red), 4 (orange), 6 (green), and 8 (cyan). Ligands with additional substitutions at positions 3 or 5 have lower affinities and include 2 (yellow), 5 (pale orange), 9 (teal), 11 (purple), 2-chloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (13) (light blue), 14 (turquoise), 15 (lilac), and 10 (dark blue). (C) The oxygen linker in the trifluoro substitution of 3 enables it to reach further into the binding pocket than 6 and confer a better lock-and-key fit in addition to forming additional hydrogen bonds with Gln286. (D) The naphthalene moiety of 12 (pink) extends as far into the binding pocket as other ligands, as shown by comparison with 9 (teal), 10 (dark blue), and 11 (purple).
Figure 7
Figure 7
Naphthalene substitution at position A of 12 enables extensive hydrophobic contacts contributed by helices 3 and 7. Shown is a superimposition of the 1 (yellow sticks) and 12 (purple sticks) compounds bound to the PPARγ LBD (green ribbons). The naphthalene moiety of 12 (purple) is more hydrophobic than other ligands, enabling unique hydrophobic interactions with the PPARγ binding pocket.

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