Advances in pharmacology最新文献

Soluble epoxide hydrolase (sEH), encoded by the EPHX2 gene, is a critical enzyme involved in the metabolism of polyunsaturated fatty acids, specifically anti-inflammatory epoxy fatty acids (EpFAs). By converting EpFAs into less active forms, sEH promotes inflammation. Preclinical data using knock-out and overexpression of the Ephx2 gene have demonstrated its key role in the development and progression of symptoms in various disease models. Inhibition of sEH increases EpFAs, thereby enhancing their anti-inflammatory effects and reducing the levels of pro-inflammatory mediators. Numerous preclinical studies suggest that sEH inhibitors show promise in reducing inflammation and its related symptoms across various diseases, highlighting their therapeutic potential. This chapter reviews the role of sEH in the development and progression of various disorders including psychiatric disorders (depression, schizophrenia, autism spectrum disorder), neurological disorders (Alzheimer's disease, Parkinson's disease, brain injury), and pain.

The pathophysiology of neurodevelopmental disorders is associated with multiple genetic and environmental risk factors. Epigenetics, owing to its potential to recover global gene expression changes associated with disease conditions, is a crucial target to address neurodevelopmental disorders influenced by genetic and environmental factors. Here, we discuss the discovery of selective inhibitors of lysine-specific demethylase 1 (LSD1) enzyme activity and their therapeutic potential for neurodevelopmental disorders through epigenetic regulation in the brain. Conventional LSD1 inhibitors not only inhibit LSD1 enzymatic activity but also interfere with LSD1-cofactor complex formation, thus leading to hematological side effects. Notably, investigations on the structure-activity relationship have revealed (aminocyclopropyl)benzamide and (aminocyclopropyl)thiophene carboxamide derivatives as novel series of LSD1 inhibitors with fewer hematological side effects. Subsequently, we discovered T-448 and TAK-418 (clinical candidate) that selectively and potently inhibit LSD1 enzymatic activity without disrupting the LSD1-cofactor complex, resulting in potent epigenetic modulation without significant hematological toxicity risks in rodents. T-448 and TAK-418, at doses that achieved almost complete LSD1 occupancy in the brain, improved behavioral abnormalities in multiple rodent models of neurodevelopmental disorders. Furthermore, comprehensive RNA expression analyses revealed that, although gene expression abnormalities exhibited limited commonality across disease models, TAK-418 normalized each aberrant gene expression pattern in these rodent models. A positron emission tomography tracer was discovered to potentially measure the occupancy of TAK-418 at the LSD1 active site in the brain to improve the translatability of its preclinical efficacy to therapeutic effects in humans. TAK-418-type LSD1 inhibitors may offer novel treatment options for neurodevelopmental disorders.

The phosphodiesterase 4 (PDE4) enzyme plays a crucial role in the central nervous system (CNS). It is extensively expressed in mammalian brain, where it regulates intracellular cyclic adenosine monophosphate (cAMP) levels. Dysregulation of PDE4 and cAMP balance is associated with various neurodegenerative diseases. By inhibiting PDE4 with drugs, cAMP levels can be stabilized, potentially improving symptoms in mental and neurological disorders such as cognition, depression, and Parkinson's disease. Mechanistically, PDE4 inhibitors exert anti-inflammatory and neuroprotective effects by increasing cAMP accumulation and activating protein kinase A (PKA). This chapter will review the relevant neurological disorders that PDE4 has been associated with and review the preclinical and clinical studies.

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a pivotal regulator of the innate immune system, orchestrates inflammatory responses implicated in neurodegenerative and inflammatory diseases. Over the past 20 years, the exploration of NLRP3 activation pathways has advanced significantly. Upon NLRP3 activation, it initiates the formation of a cytosolic multiprotein complex known as the inflammasome. This complex activates caspase-1, which then processes proinflammatory cytokines IL-1β and IL-18 and leads to gasdermin-mediated cell death, pyroptosis. Structural insights into NLRP3 inflammasome assembly and caspase-1 activation have spurred development of novel small molecule inhibitors targeting this pathway, aiming to mitigate excessive inflammation without compromising immune surveillance. The initial NLRP3 inhibitor reported was glyburide, an FDA-approved antidiabetic drug of the sulfonylurea class, which was found to inhibit the release of IL-1β induced by stimuli in human monocytes and murine macrophages. Subsequently, MCC950 (also known as CRID3), a direct NLRP3 inhibitor, was discovered. While showing promising results in preclinical and clinical trials for treating diseases, higher doses of MCC950 led to elevated transaminase levels and hepatotoxicity concerns. Recent studies using MCC950 as a research tool have prompted the development of safer and more effective NLRP3 inhibitors, including a series of compounds currently undergoing clinical trials, highlighting the potential of NLRP3 inhibitors in attenuating disease progression and improving therapeutic outcomes. In this chapter, we delve into the latest progress in understanding the mechanism of NLRP3 inflammasome activation and its roles in the pathophysiology of neurological diseases. We also summarize recent development of small molecule NLRP3 inhibitors along with the associated obstacles and concerns.

Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.

Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.

Cognitive deficits are a class of symptoms present in a broad range of disorders that go largely unaddressed by current medications. Disruptions in executive function and memory can be detrimental to patient quality of life, so there is a large unmet medical need for novel therapies to improve cognitive performance. Recent research has highlighted the importance of the type II metabotropic glutamate receptor 3 (mGluR3) in patterns of persistent neuronal firing in the dorsolateral prefrontal cortex of primates, a region critical for higher order cognitive processes. The selective, endogenous agonist of the mGlu3 receptor is N-acetylaspartyl glutamate (NAAG). NAAG is hydrolyzed by the enzyme glutamate carboxypeptidase II (GCPII) which is highly upregulated in neuroinflammatory conditions. Inhibition, GCPII has been investigated as a promising therapeutic avenue in a range of preclinical models and the relationship between NAAG and cognitive function has been studied in multiple clinical populations. The following chapter summarizes the body of preclinical and clinical work supporting the inhibition of GCPII to improve cognitive deficits and the drug discovery approaches that have been utilized to improve pharmacokinetics and brain penetration for future clinical translation of GCPII inhibitor.

D-amino acid oxidase (DAAO) is a flavin-dependent peroxisomal monooxygenase with a substrate preference for glycine and certain small hydrophobic D-amino acids. Although the biochemical properties of the enzyme have been extensively studied since 1930s, the therapeutic interest in targeting the enzyme emerged more recently after the physiological significance of endogenous D-serine, a substrate for DAAO, was recognized in 1990s. This triggered a new wave of efforts by many researchers to develop more potent and drug-like DAAO inhibitors with greater translational potential. This chapter recounts the evolution of DAAO inhibitors since then driven by new molecular design strategies guided by structural biology. Some of these inhibitors were investigated in a range of preclinical in vivo studies to assess pharmacokinetics, pharmacodynamics, and behavioral pharmacology. Most importantly, these efforts culminated with the discovery of TAK-831 (luvadaxistat), an orally available brain-penetrant DAAO inhibitor currently under clinical development, representing a true bench-to-bedside success in this field.

Current FDA-approved drugs for neurodegenerative diseases primarily aim to reduce pathological protein aggregation or alleviate symptoms by enhancing neurotransmitter signaling. However, outcomes remain suboptimal and often fail to modify the course of neurodegenerative diseases. Acute neurologic injury that occurs in stroke and traumatic brain injury (TBI) also suffer from inadequate therapies to prevent neuronal cell death, resulting from both the acute insult and the subsequent reperfusion injury following recanalization of the occlusion in stroke. Approaches to prevent neuronal loss in neurodegenerative disease and acute neurologic injury hold significant therapeutic promise. Parthanatos is a cell death pathway that is activated and plays an integral role in these neurologic disorders. Parthanatos-associated apoptosis-inducing factor nuclease (PAAN), also known as macrophage migration inhibitory factor (MIF) nuclease, is the final executioner in the parthanatic cell death cascade. We posit that inhibiting parthanatos by blocking MIF nuclease activity offers a promising and precise strategy to prevent neuronal cell death in both chronic neurodegenerative disease and acute neurologic injury. In this chapter, we discuss the role of MIF's nuclease activity - distinct from its other enzymatic activities - in driving cell death that occurs in various neurological diseases. We also delve into the discovery, screening, structure, and function of MIF nuclease inhibitors, which have demonstrated neuroprotection in Parkinson's disease (PD) cell and mouse models. This analysis includes essential future research directions and queries that need to be considered to advance the clinical development of MIF nuclease inhibitors. Ultimately, our discussion aims to inspire drug development centered around inhibiting MIF's nuclease activity, potentially resulting in transformative, disease-modifying therapeutics.