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1.
Bioorg Chem ; 144: 107114, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38224637

RESUMEN

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.


Asunto(s)
Leucemia Mieloide Aguda , Inhibidores de Fosfodiesterasa , Pirazoles , Pirimidinonas , Adulto , Humanos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , GMP Cíclico/metabolismo
2.
Sheng Li Xue Bao ; 75(1): 91-98, 2023 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-36859838

RESUMEN

The ovary is the reproductive organ of female mammals, which is responsible for producing mature eggs and secreting sex hormones. The regulation of ovarian function involves the ordered activation and repression of genes related to cell growth and differentiation. In recent years, it has been found that histone posttranslational modification can affect DNA replication, damage repair and gene transcriptional activity. Some regulatory enzymes mediating histone modification are co-activators or co-inhibitors associated with transcription factors, which play important roles in the regulation of ovarian function and the development of ovary-related diseases. Therefore, this review outlines the dynamic patterns of common histone modifications (mainly acetylation and methylation) during the reproductive cycle and their regulation of gene expression for important molecular events, focusing on the mechanisms of follicle development and sex hormone secretion and function. For example, the specific dynamics of histone acetylation are important for the arrest and resumption of meiosis in oocytes, while histone (especially H3K4) methylation affects the maturation of oocytes by regulating their chromatin transcriptional activity and meiotic progression. Besides, histone acetylation or methylation can also promote the synthesis and secretion of steroid hormones before ovulation. Finally, the abnormal histone posttranslational modifications in the development of two common ovarian diseases (premature ovarian insufficiency and polycystic ovary syndrome) are briefly described. It will provide a reference basis for understanding the complex regulation mechanism of ovarian function and further exploring the potential therapeutic targets of related diseases.


Asunto(s)
Código de Histonas , Histonas , Femenino , Animales , Procesamiento Proteico-Postraduccional , Ovario , Oocitos , Mamíferos
3.
Expert Opin Ther Pat ; 32(4): 423-439, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35016587

RESUMEN

INTRODUCTION: PDE1 has been demonstrated to be a potential drug target for a variety of diseases, such as Alzheimer's disease and cardiovascular disease. In the past decades, numerous PDE1 inhibitors with structural diversities have been developed and patented by pharmaceutical companies, providing drug candidates for exploring novel disease indications of PDE1. AREA COVERED: This review aims to provide an overview of PDE1 inhibitors reported in patents from 2008 to present. EXPERT OPINION: Among current PDE1 inhibitors, only a few of them showed high selectivity over other PDEs, which might cause severe side effects in the clinic. The development of highly selective PDE1 inhibitors is still the 'top priority' in the following research. The selective recognition mechanism of PDE1 with inhibitors should be further elucidated by X-ray crystallography in order to provide evidence for the rational design of selective PDE1 inhibitors. In addition, PDE1 inhibitors should be applied to different clinical indications beyond CNS diseases.


Asunto(s)
Enfermedad de Alzheimer , Patentes como Asunto , Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Humanos
4.
Bioorg Med Chem Lett ; 41: 128016, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33838306

RESUMEN

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer's disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure-activity relationship (SAR) of lead compounds.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/farmacología , Descubrimiento de Drogas , Inhibidores de Fosfodiesterasa/farmacología , Enfermedad de Alzheimer/metabolismo , Antioxidantes/síntesis química , Antioxidantes/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2 , Relación Dosis-Respuesta a Droga , Fluoresceínas/análisis , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad
5.
J Med Chem ; 63(14): 7867-7879, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32603117

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as a novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on the PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 of 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, and remarkable pharmacodynamic effects as an anti-IPF agent. Oral administration of compound 3m (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model and prevented transforming growth factor-ß-induced fibroblast-to-myofibroblast conversion in vitro, indicating that PDE1 inhibition could serve as a novel target for the efficient treatment of IPF.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinonas/uso terapéutico , Animales , Bleomicina , Diferenciación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Masculino , Estructura Molecular , Miofibroblastos/efectos de los fármacos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Unión Proteica , Pirazoles/síntesis química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Pirimidinonas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Termodinámica
6.
Bioorg Med Chem Lett ; 30(14): 127254, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32527553

RESUMEN

Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer's disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC50 of 2.0 nM against PDE9, showed good metabolic stability (t1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.


Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Fármacos Neuroprotectores/farmacología , Pirazoles/farmacología , Pirimidinonas/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Enfermedad de Alzheimer/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad
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