Glycolipid metabolism is a crucial physiological process that provides both energy and essential biomaterials for the body. Maintaining homeostasis and precise regulatory control is vital for sustaining overall health. With shifts in lifestyle and nutritional habits, the incidence of major metabolic disorders characterized by dysregulation of glucose and lipid metabolism-such as diabetes, fatty liver disease, obesity, atherosclerosis, and cardiovascular disease-has increased steadily in recent years. Consequently, elucidating the physiological mechanisms underlying glucose and lipid metabolism, as well as identifying novel therapeutic targets for metabolic diseases, has become a major research focus. Phosphodiesterases (PDEs) have emerged as promising targets for modulating glucose and lipid metabolism by regulating intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways. This review summarizes the molecular structure, subcellular localization, and signaling mechanisms of PDEs involved in the regulation of glucose and lipid metabolism and energy homeostasis. Furthermore, it highlights recent advances in the development and pharmacological evaluation of PDE inhibitors in animal models of metabolic disorders. Emphasis is placed on the roles of PDE inhibition in modulating metabolic pathways, providing a theoretical foundation for the development of potential therapeutics targeting glucose- and lipid-related metabolic diseases.

2025-12-01·JOURNAL OF NEUROCHEMISTRY

Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism

Article

作者: d’Anglemont de Tassigny, Xavier ; Jiménez‐Medina, Alejandro ; López‐López, Ivette ; López‐Barneo, José

ABSTRACT:

Glial cell line‐derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic adenosine monophosphate (cAMP)‐dependent signaling, a compelling strategy for PD treatment is the pharmacological elevation of intracellular cAMP. This approach aims to enhance endogenous GDNF, offering potential neuroprotective benefits. In this study, we show that selective inhibition of phosphodiesterases (PDEs) subtypes, therefore enhancing intracellular cAMP levels, increases Gdnf mRNA expression in striatal slices ex vivo; however, achieving this effect in vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non‐selective PDE inhibitor. Ibudilast robustly upregulated striatal Gdnf expression both ex vivo and in vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase‐positive (TH+) neurons in the substantia nigra, attenuation of TH+ fiber loss in the striatum, and mitigation of striatal dopamine depletion. Given its established clinical use and favorable safety profile, these findings support further investigation of Ibudilast as a potential disease‐modifying therapy in PD. image

2025-12-01·Alzheimers & Dementia

Advancing PDE Inhibition: Preclinical Perspectives, Clinical Applications, and Future Therapeutics

Review

作者: Kamboj, Vaishali

Abstract:

Background:

The phosphodiesterase enzyme family controls how much cyclic nucleotides such as cAMP and cGMP stay within cells. Research shows that blocking PDE enzyme activity helps treat many health problems including heart conditions, brain diseases, breathing disorders, and tumors. The medical industry has put several PDE inhibitors (PDEIs) into clinical use to treat erectile dysfunction with sildenafil, pulmonary hypertension with tadalafil, and chronic obstructive pulmonary disease with roflumilast. Research continues to address the problems of enzyme specificity and unintended reactions plus overall treatment safety.

Method:

Our review brings together discovery results from both bench and bedside studies on PDE inhibitors. Our research included studies that tested how PDEIs work in the body and what results they provide at different safe usage levels. Our team studied PDEIs impact on biological signaling both in test tubes and living organisms then reviewed patient results to establish treatment methods and safe dosing. Our team used computer‐based modeling and structure‐activity analysis to find new PDE blockers that work better and are safer.

Results:

Test studies proved that directly targeting PDE enzymes controls inflammation, protects nerve cells and relaxes blood vessels. Research has demonstrated promising results from rolipram a PDE4 inhibitor in brain disease testing while PDE5 inhibitors demonstrate effective heart protection and vessel relaxation in experiments. Clinical trials proved PDEIs work but doctors hesitate to use them because PDE4 inhibitors cause nausea and PDE5 inhibitors lead to low blood pressure. Scientists study new forms of PDE inhibitors to improve patient results and limit treatment side effects.

Conclusion:

Using PDE inhibitors as treatment continues to show promise across increasing medical applications. Although present PDEIs benefit patients we need new studies that make these inhibitors more selective for specific isoforms and with fewer unwanted effects to create improved therapeutic drugs. Emerging technology in drug discovery including artificial intelligence and personalized treatment methods will guide the creation of better and safer PDE inhibitors to treat many diseases.

项与 PDE inhibitors(Promega Corp.) 相关的新闻（医药）

2026-01-09

·Business Wire

Enthorin Therapeutics Announces Initiation of Phase II Clinical Trial of MRM-3379 (Formerly ENT-3379) for Fragile X Syndrome by Licensing Partner Mirum Pharmaceuticals

ESCONDIDO, Calif.--(BUSINESS WIRE)--Enthorin Therapeutics, LLC, a biotechnology company focused on circuit-modulating treatments for neurological and neurodevelopmental disorders, announced that its licensing partner for MRM-3379 (formerly ENT-3379), Mirum Pharmaceuticals, Inc. (NASDAQ: MIRM), in December, reported the initiation of the BLOOM Phase 2 clinical study evaluating MRM-3379 in Fragile X syndrome (FXS). MRM-3379 is an orally available, highly brain-penetrant, selective phosphodiesterase-4D (PDE4D) inhibitor designed to enhance cAMP signaling. The compound was discovered by scientists at Dart Neuroscience (DNS), including current members of Enthorin Therapeutics, and advanced through Phase 1 clinical development at DNS. Preclinical data, including results from an FMR1 knockout mouse model of Fragile X syndrome, suggest that MRM-3379 improves cognition and alleviates behavioral deficits across multiple domains. The entry of MRM-3379 into Fragile X patient trials by Mirum Pharmaceuticals is the culmination of over a decade of diligent scientific research and development by the clinicians and scientists at Enthorin and DNS. Enthorin wants to acknowledge all of the dedicated clinical and scientific staff who participated in the discovery and development of MRM-3379. About Enthorin Therapeutics Enthorin Therapeutics is a clinical stage pharmaceutical company founded with the goal of developing innovative therapeutics that target brain circuit dysfunction to improve quality of life for patients, families, and communities. The company develops therapies designed to restore neural plasticity and network function in neurological and neurodevelopmental diseases. The company’s pipeline includes MRM-3379 which is licensed to Mirum Pharmaceuticals; ENT-7340, an IND enabled PDE2A inhibitor for the potential treatment of intellectual and developmental disabilities; ENT-2675 for treatment of Parkinson’s disease MCI and dyskinesia; and a portfolio of GABA alpha 5 negative allosteric modulators for the potential treatment of Dup15q syndrome. Enthorin leverages translational neurobiology, pharmacology and advanced imaging to bridge pre-clinical and clinical development. Learn more at www.enthorin.com About Fragile X Syndrome Fragile X syndrome is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It affects approximately 1 in 4,000 males and 1 in 8,000 females. At present there are no approved treatments that target the underlying biology of Fragile X available. The syndrome manifests in developmental delays, learning difficulties, anxiety, hyperactivity and autistic-like behaviors. PDE inhibitors aim to elevate cyclic AMP (cAMP) levels, rebuild neural signaling networks and restore synaptic plasticity—a pathway particularly relevant in Fragile X and other intellectual and developmental disabilities (IDD). More information about PDE inhibitors and Fragile X is available at: https://www.fraxa.org/fragile-x-and-pde-inhibitors-a-promising-path-forward-for-brain-disorders/

临床1期临床2期引进/卖出临床结果

100 项与 PDE inhibitors(Promega Corp.) 相关的药物交易

登录后查看更多信息