Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo

Ham, Jungyeob; Hwang, Hoosang; Kim, Euno; Kim, Jeong Ah; Cho, Sung Jin; Ko, Jaeyoung; Lee, Woojin; Lee, John J.; Holla, Harish; Banerjee, Joydeep; Kim, Seokho; Yang, Inho; Lee, Hyun Joo; Shin, Kyoungjin; Choi, Hyukjae; Nam, Sang Jip; Tak, Jungae; Hahn, Dongyup; Oh, Taekyung; Won, Dong Hwan; Lee, Tae Gu; Choi, Jihye; Park, Mi Sun; Seok, Chaok; Chin, Jungwook; Kang, Heonjoong

doi:10.1016/j.ejmech.2012.03.055

Cited by 12 publications

(4 citation statements)

References 36 publications

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“…From the results of the in vivo experiment in atherosclerosis mouse models, compound 29 was considered as a potential agent for the treatment of atherosclerosis. In 2012, Ham et al 164 reported a synthesis of novel Y-shaped PPARδ-selective agonists by substituting alkyl or aryl groups at the α-position of sulfide. Compounds 30, 31, and 32 exhibited highly potent and selective PPARδ agonistic activity and were proposed as safer potential candidates for the treatment of obesity.…”

Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

“…Compound 30 showed strong PPARδ agonistic activity (EC 50 = 1.6 nM) with 625-and 6250-fold selectivity over PPARα and PPARγ. 164 Notably, some structurally different novel compounds have been discovered as highly selective PPARδ agonists using ligand-based machine learning and structural modeling techniques. Among these compounds, 33 (GNF-0242), with an amide linker moiety, showed the most selective PPARδ agonist activity (EC 50 = 4 nM).…”

Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

“…Moreover, a Y-shaped PPARδ selective agonist ( 30 ) prepared by substituting the halophenyl group at the α-position of the sulfide also exhibited improved activity and PPARδ selectivity. Compound 30 showed strong PPARδ agonistic activity (EC 50 = 1.6 nM) with 625- and 6250-fold selectivity over PPARα and PPARγ . Notably, some structurally different novel compounds have been discovered as highly selective PPARδ agonists using ligand-based machine learning and structural modeling techniques.…”

Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

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Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

et al. 2020

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One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARβ or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor’s structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.

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Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

Section: Medicinal Chemistry Of Synthetic Pparδ Agonistsmentioning

confidence: 99%

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Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

et al. 2020

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“…A sustainable change in lifestyle, including dieting and physical exercise, is the pillar for the treatment of obesity that can be complemented by gastric balloon and bariatric surgery to assist weight loss4 and by taking anti-obesity drugs to reduce appetite or fat absorption567. However, dieting often shows limited success8, surgery is associated with significant risks9 and only some anti-obesity drugs with modest efficacy10 remain on the market after many have been withdrawn because of side effects11121314, and few have entered clinical trials since15. The amylin analogue pramlintide has recently been licensed as injection-based adjunctive type 2 diabetes therapy16, as it reduces adsorption of glucose and other nutrients such as fat by slowing gastric emptying, promotes satiety via GLP-1-independent hypothalamic receptors and inhibits inappropriate secretion of glucagon17.…”

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confidence: 99%

A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice

2013

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Diet-induced obesity is a lifestyle-associated medical condition that increases the risk of developing cardiovascular disease, type 2 diabetes and certain types of cancer. Here we report the design of a closed-loop genetic circuit that constantly monitors blood fatty acid levels in the setting of diet-associated hyperlipidemia and coordinates reversible and adjustable expression of the clinically licensed appetite-suppressing peptide hormone pramlintide. Grafting of the peroxisome proliferator-activated receptor-α onto the phloretin-responsive repressor TtgR produces a synthetic intracellular lipid-sensing receptor (LSR) that reversibly induces chimeric TtgR-specific promoters in a fatty acid-adjustable manner. Mice with diet-induced obesity in which microencapsulated cells engineered for LSR-driven expression of pramlintide are implanted show significant reduction in food consumption, blood lipid levels and body weight when put on a high-fat diet. Therapeutic designer circuits that monitor levels of pathologic metabolites and link these with the tailored expression of protein pharmaceuticals may provide new opportunities for the treatment of metabolic disorders.

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Engineering Mammalian Designer Cells for the Treatment of Metabolic Diseases

Wang

Dong

et al. 2017

Biotechnology Journal

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Synthetic biology applies engineering principles to biological systems and has significantly advanced the design of synthetic gene circuits that can reprogram cell activities to perform new functions. The ability to engineer mammalian designer cells with robust therapeutic behaviors has brought new opportunities for treating metabolic diseases. In this review, the authors highlight the most recent advances in the development of synthetic designer cells uploaded with open- or closed-loop gene circuits for the treatment of metabolic disorders including diabetes, hypertension, hyperuricemia, and obesity, and discuss the current technologies and future perspectives in applying these designer cells for clinical applications. In the future, more and more rationally designed cells will be constructed and revolutionized to treat a number of metabolic disorders in an intelligent manner.

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Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo

Cited by 12 publications

References 36 publications

Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective

A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice

Engineering Mammalian Designer Cells for the Treatment of Metabolic Diseases

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