Pharmacological Research - Natural Products, Год журнала: 2023, Номер 1, С. 100006 - 100006
Опубликована: Ноя. 28, 2023
Язык: Английский
Bioorganic Chemistry, Год журнала: 2024, Номер 145, С. 107191 - 107191
Опубликована: Фев. 10, 2024
Язык: Английский
Процитировано
2
Alzheimer s & Dementia, Год журнала: 2024, Номер unknown
Опубликована: Авг. 21, 2024
Abstract INTRODUCTION CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers mild moderate AD from two independent trials. METHODS Unbiased analysis tandem‐mass tag mass spectrometry (TMT‐MS) quantitative proteomics, pathway and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed SPARC cohort (NCT03493282). Comparative a meta‐analysis interim SHINE (NCT03507790; SHINE‐A) followed by network (weighted gene co‐expression [WGCNA]) used understand biological impact CT1812. RESULTS pathways identified that replicate across cohorts. The revealed novel candidate linked S2R biology AD, treatment‐associated networks driven S2R. DISCUSSION Early validation replicating cohorts strengthens understanding patients supports CT1812's synaptoprotective mechanism action its continued development. Highlights This study (NCT03493282) trials/cohorts Two Ph2 trial (SPARC [NCT03507790; SHINE‐A]) Amyloid beta (Aβ) & synaptic impacted treatment‐related correlates emerge Network sigma‐2 receptor (S2R)‐interacting proteins may be “drivers” changes
Язык: Английский
Процитировано
2
Cellular Signalling, Год журнала: 2024, Номер 116, С. 111069 - 111069
Опубликована: Янв. 28, 2024
Язык: Английский
Процитировано
2
Medicinal Research Reviews, Год журнала: 2024, Номер unknown
Опубликована: Сен. 19, 2024
Abstract Since the first discovery of antipsychotics in 1950s, targeting dopaminergic drugs has manifested to well manage positive symptoms schizophrenia with limited efficacy for negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards development innovative agents that can effectively stabilize dopamine serotonin systems or target nondopaminergic pathways, leading various promising drug candidates entering into clinical trials. Notably, sigma‐2, 5‐HT 2A , α 1A receptor antagonist roluperidone, as a fixed‐dose combination M 1/4 agonist KarXT, submitted NDA applications. The dual ulotaront, which targets TAAR1 receptors, GlyT1 inhibitor iclepertin advanced phase 3 Nevertheless, satisfactory therapeutic strategies remain elusive. This review highlights current endeavors developing novel chemical small‐molecule entities combinations treatment since 2017, thus facilitating efficient next generation antipsychotics.
Язык: Английский
Процитировано
2
Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(17), С. 12499 - 12519
Опубликована: Авг. 22, 2023
The synthesis and pharmacological activity of a new series isoxazolylpyrimidines as sigma-2 receptor (σ2R) ligands are reported. Modification hit retrieved in an HTS campaign allowed the identification compound WLB-89462 (20c) with good σ2R affinity (Ki = 13 nM) high selectivity vs both σ1R 1777 general panel 180 targets. It represents one first drug-like properties, linked to physicochemical ADMET profile (good solubility, no CYP inhibition, metabolic stability, permeability, brain penetration, oral exposure rodents). Compound 20c shows neuroprotective vitro improves short-term memory impairment induced by hippocampal injection amyloid β peptide rats. Together promising effects chronic models where is currently being evaluated, these results pave way toward its clinical development agent.
Язык: Английский
Процитировано
5
International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(19), С. 14672 - 14672
Опубликована: Сен. 28, 2023
Sigma receptors are non-opiate/non-phencyclidine that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane membranes of endoplasmic reticulum, mitochondria, nucleus. Until recently, biology/pharmacology these proteins focused primarily on their role neuronal functions brain/retina. However, there have been recent developments field with discovery unexpected roles for iron/heme homeostasis. receptor 1 (S1R) regulates oxidative stress-related transcription factor NRF2 protects against ferroptosis, an iron-induced cell death process. 2 (S2R), which is structurally to S1R, complexes components PGRMC1 PGRMC2. S2R, PGRMC1, PGRMC2, either independently or as protein–protein complexes, elicit a multitude effects profound influence This includes regulation secretion iron-regulatory hormone hepcidin, modulation activity mitochondrial ferrochelatase, catalyzes iron incorporation into protoporphyrin IX form heme, chaperoning specific hemoproteins thereby influencing biological stability, protection ferroptosis. Consequently, PGRMC2 potentiate disease progression hemochromatosis cancer. These new discoveries usher this intriguing group non-traditional unchartered territory biology medicine.
Язык: Английский
Процитировано
5
The Journal of Prevention of Alzheimer s Disease, Год журнала: 2024, Номер unknown
Опубликована: Янв. 1, 2024
Язык: Английский
Процитировано
1
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 281, С. 117037 - 117037
Опубликована: Ноя. 10, 2024
Язык: Английский
Процитировано
1
Analytical Chemistry, Год журнала: 2024, Номер unknown
Опубликована: Дек. 24, 2024
Lipid rafts are liquid-ordered domains in which specific enzymes and receptors located. These membrane platforms play crucial roles a variety of signaling pathways. Alterations the lipid environment, such as those elicited by oxidative stress, can lead to important functional disruptions proteins. Cell microarrays have emerged past decade powerful methodology for study both lipids proteins at large scales. Based on that technology importance subdomains, we developed new printed raft with preserved native protein structure environment. To validate this evaluate its potential different aims, (RMMAs) containing two cell types (astrocytes neurons) three conditions control situation, metabolic stress) were developed. differences profiles between domains, MALDI-MS assay was performed RMMAs. preservation activities (enzymatic activity ligand binding) NADH oxidoreductase, GAPDH, cholinesterase activities, sigma-1 sigma-2 binding assays performed. We demonstrate performance microarray technology, adapted valid explore changes composition from brain lines under stress relevant neuropathology.
Язык: Английский
Процитировано
0
Ophthalmic surgery, lasers & imaging retina, Год журнала: 2024, Номер 55(9), С. 528 - 534
Опубликована: Июнь 25, 2024
Dry age-related macular degeneration (AMD) has been historically managed with lifestyle modifications, monitoring for conversion to wet AMD, and vitamins. Recently there a flurry of research focused on discovering new targets prevent worsening dry AMD. In 2023, the US Food Drug Administration approved first two intravitreal complement inhibitors slow rate geographic atrophy progression. However, serial injections chronic progressive disease are burdensome patients have procedural risks. Therefore, is significant discover novel oral medications manage Several currently in phase 2 3 clinical trials whereas others had recent readouts their efficacy. The purpose this review describe therapeutic pathways being investigated provide an update status management
Язык: Английский
Процитировано
0