Design, development and evaluation of novel dual PPARδ/PPARγ agonists

Gathiaka, Symon; Nanayakkara, Gayani; Boncher, Tracey; Acevedo, Orlando; Wyble, Johnathon; Patel, Sagar P.; Patel, Akash; Shane, Mary Elizabeth; Bonkowski, Blake; Wieczorek, Jason; Rong, Yinghui; Huggins, Kevin W.; Smith, Forest; Amin, Rajesh

doi:10.1016/j.bmcl.2012.11.060

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…A novel compound 50 (Figure ) was obtained from 23 potent ligands by docking into the PPAR γ/δ LBDs. This new compound showed significant efficacy for PPARγ and PPARδ in the luciferase and gene expression studies by Symon Gathiaka et al . It has been known that Tyr473 in PPARγ pocket would inevitably lead to lipogenesis.…”

Section: Ppar γ/δ Dual Agonistsmentioning

confidence: 99%

Multitargeted bioactive ligands for PPARs discovered in the last decade

et al. 2016

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Type 2 diabetes took insulin resistance as the main clinical manifestation. PPARs have been reported to be the therapeutic targets of metabolic disorders, such as obesity, hypertension, diabetes, and cardiovascular disease. Previously, PPARγ agonist rosiglitazone was restricted in clinic due to cardiomyocytes infarction, weight gain, and other serious side-effects, which were mainly due to the single and selective PPARγ agonism. In recent years, multitarget-directed PPAR agonists with synergistic reaction as well as fewer side-effect have been the hot topic in designing promising agents. In this review, we updated and generalized the development of PPARγ partial agonists, PPARγ antagonists, PPARα/γ dual agonists, PPARδ partial agonists, PPARδ antagonists, PPARα/δ dual agonists, PPARγ/δ dual agonists, and PPARα/γ/δ pan-agonists published in recent decade. Most of these molecules were modified from known structures or came from high-throughput screening. Among these molecules, some were expected to be promising drugs against metabolic disorders, while others seemed to provide new insight for designing novel PPAR agents.

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Section: Ppar γ/δ Dual Agonistsmentioning

confidence: 99%

Multitargeted bioactive ligands for PPARs discovered in the last decade

et al. 2016

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“…Selective PPAR γ modulators (SPPAR γ Ms) have attracted considerable attention because of their ability to selectively target PPAR γ activity states. Several investigators have characterized and identified promising SPPAR γ Ms that serve as partial agonists for PPAR γ in cell based transcriptional activity and adipogenic assays [ 167 , 168 ]. SPPAR γ Ms specifically bind to the LBD of PPAR γ via an activation function 2 motif (AF2).…”

Section: Ppar γ Agonistsmentioning

confidence: 99%

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

et al. 2018

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Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

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“…We have rationally developed a novel dual PPARδ/γ agonist in silico. Twenty-three nontraditional lead compounds were designed, synthesized, and tested [ 14 ]. The design of the PPARγ compounds was based on avoiding the tyrosine-473 site in the AF2 ligand binding domain.…”

Section: Introductionmentioning

confidence: 99%

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease

Steinke

Govindarajulu

Pinky

et al. 2023

Cells

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Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer’s disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

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Design, development and evaluation of novel dual PPARδ/PPARγ agonists

Cited by 10 publications

References 28 publications

Multitargeted bioactive ligands for PPARs discovered in the last decade

Multitargeted bioactive ligands for PPARs discovered in the last decade

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease

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