Novel Indole-Based Peroxisome Proliferator-Activated Receptor Agonists:  Design, SAR, Structural Biology, and Biological Activities

Abstract

The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKA(y) mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARgamma and could be an important moiety for the binding to the protein.

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

“…Most pan-PPAR agonists, including GW677954, DRL-11605, PLX-204, GW625019 and netoglitazone, have been discontinued because of safety problems [18][19][20]. Additionally, preclinical studies on pan-PPAR agonists LY465608 and BPR1H036 are not progressing smoothly [21][22][23][24].…”

The application of molecular modelling in the safety assessment of chemicals: A case study on ligand-dependent PPARγ dysregulation

“…The final conformer for each ligand was selected from the output set of up to 10 best poses retained after its docking according to two criteria: (i) visual inspection relative to the corresponding structurally similar template -the PDB ligand used as scaffold in structure generation or the ligand UNT from 3IA6 PDB complex as one of the most active agonists with pEC50 = 7.886 and 103% relative efficacy and possessing structural features from among most of the structures that are typical features of the agonists (Casimiro-Garcia et al, 2009;Mahindroo et al, 2005); (ii) the value of the docking score (the smallest negative scores were preferred). The ligands extracted from the PDB complexes were maintained in their experimental bioactive conformations.…”

Structural Basis for the Improved Potency of Peroxisome Proliferator‐Activated Receptor (PPAR) Agonists

“…According to previous reports, [3a] the H-bonds contributed to the stabilized interactions of activation function helix 2 (AF-2 Helix) in PPARg, and this helped to recruit coactivators and activate the PPAR transcription function of downstream target genes. The indole head of 15-located around helixes 3, 5, 7, and 10 of the PPARg LBD-formed hydrophobic interactions with Phe282 and Cys285 on helix 3 and [10] III F 0.01 0.23 0.01 12 [10] III G 0.02 0.29 0.08 13 [11] IV A 0.12 0.65 > 10 14 [11] His449 on helix 10. The linker of 15 formed hydrophobic interactions with Leu330 on helix 5.…”

“…Figure 1 a shows the general design of PPAR agonists; they comprise an acidic group attached to an aromatic part, which in turn linked to the aromatic tail through a spacer. Our previous studies focused on the use of indole [10][11][12] and 1,2,3,4-tetrahydroquinoline as the head parts, [11] along with various aromatic tail parts to obtain potent PPAR agonists with varying levels of selectivity toward a, g and d subtypes. We recently reported the identification of 4-phenylbenzophenone as a novel tail-part building block that confers selective and potent PPARg agonist activity when incorporated into both indole and tetrahydroquinoline series of compounds through N-linkages, while the acidic head group is linked through an oxygen bridge (Figure 1 b).…”