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1.
J Med Chem ; 62(8): 4218-4224, 2019 04 25.
Article in English | MEDLINE | ID: mdl-30916555

ABSTRACT

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Drug Design , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Binding Sites , Catalytic Domain , Dementia, Vascular/drug therapy , Dementia, Vascular/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Maze Learning/drug effects , Mice , Molecular Docking Simulation , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyridines/chemistry , Pyridines/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
2.
J Med Chem ; 61(18): 8468-8473, 2018 09 27.
Article in English | MEDLINE | ID: mdl-30148362

ABSTRACT

To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.


Subject(s)
Hypertension, Pulmonary/drug therapy , Microsomes, Liver/drug effects , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/pharmacology , Pulmonary Artery/drug effects , Administration, Oral , Animals , Crystallography, X-Ray , ERG1 Potassium Channel/antagonists & inhibitors , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Microsomes, Liver/metabolism , Microsomes, Liver/pathology , Models, Molecular , Molecular Structure , Phosphodiesterase 5 Inhibitors/chemistry , Protein Conformation , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Structure-Activity Relationship
3.
Int J Mol Sci ; 19(6)2018 Jun 05.
Article in English | MEDLINE | ID: mdl-29874838

ABSTRACT

Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span⁻extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Forkhead Transcription Factors/genetics , Hydroxybenzoates/pharmacology , Longevity/genetics , Receptor, Insulin/genetics , Aging/drug effects , Aging/genetics , Aging/physiology , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/physiology , Caloric Restriction , Humans , Longevity/drug effects , Mutation , Oxidative Stress/drug effects , Oxidative Stress/genetics
4.
J Med Chem ; 60(15): 6622-6637, 2017 08 10.
Article in English | MEDLINE | ID: mdl-28686445

ABSTRACT

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.


Subject(s)
Chromones/therapeutic use , Hypertension, Pulmonary/drug therapy , Phosphodiesterase 5 Inhibitors/therapeutic use , Pyrroles/therapeutic use , Animals , CHO Cells , Catalytic Domain , Chromones/administration & dosage , Chromones/chemical synthesis , Chromones/pharmacokinetics , Cricetulus , Cytochrome P-450 CYP1A2 Inhibitors/administration & dosage , Cytochrome P-450 CYP1A2 Inhibitors/chemical synthesis , Cytochrome P-450 CYP1A2 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP1A2 Inhibitors/therapeutic use , Drug Stability , ERG1 Potassium Channel/antagonists & inhibitors , Female , Humans , Male , Mice , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/chemical synthesis , Phosphodiesterase 5 Inhibitors/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats, Sprague-Dawley , Rats, Wistar , Sildenafil Citrate/pharmacology , Structure-Activity Relationship
5.
Molecules ; 21(8)2016 Aug 22.
Article in English | MEDLINE | ID: mdl-27556437

ABSTRACT

This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butyl hydroperoxide (TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM + 10% FBS for 24 h and pretreated with different concentrations of MDHB or N-acetyl-l-cysteine (NAC) for 4 h prior to the addition of 40 µM TBHP for 24 h. Cell viability was analyzed using the methylthiazolyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rates. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells.


Subject(s)
DNA Damage/drug effects , Hydroxybenzoates/pharmacology , Neurons/cytology , Neuroprotective Agents/pharmacology , tert-Butylhydroperoxide/adverse effects , Acetylcysteine/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival , Gene Expression Regulation/drug effects , Glutathione Peroxidase/metabolism , Humans , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/drug effects , Superoxide Dismutase/metabolism
6.
Exp Gerontol ; 60: 108-16, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25456844

ABSTRACT

To identify and analyze the compounds that delay aging and extend the lifespan is an important aspect of the gerontology research. A number of compounds, including the ones with the antioxidant properties, have been shown to extend the lifespan of Caenorhabditis elegans. Here, we report that methyl 3,4-dihydroxybenzoate (MDHB), a small antioxidant molecule, prolongs the C. elegans' lifespan under normal as well as stress conditions, delays the age-associated decline in the pharyngeal pumping rate, and obviously enhances the abilities of scavenging intracellular reactive oxygen species (ROS). To further investigate the mechanism underlying the anti-aging action of MDHB, microarray analyses were performed, which demonstrated that 13 genes were differentially expressed in worms treated with MDHB for 48 and 144 h in common. RNA interference of W06A7.4 (NM_001269697.1), the most significantly up-regulated gene, shortened the lifespan of worms by 14%, compared with the L4440 control. Our findings demonstrate that W06A7.4 is a potentially positive determinant of the MDHB induced C. elegans' lifespan extension effect.


Subject(s)
Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Genes, Helminth/drug effects , Hydroxybenzoates/pharmacology , Longevity/drug effects , Longevity/genetics , Aging/drug effects , Aging/genetics , Aging/physiology , Animals , Antioxidants/pharmacology , Caenorhabditis elegans/physiology , Longevity/physiology , RNA Interference , RNA, Helminth/genetics , RNA, Helminth/metabolism , Reactive Oxygen Species/metabolism , Transcriptome
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