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1.
Org Lett ; 22(2): 584-588, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31904969

RESUMO

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 µM).

2.
Chem Biodivers ; 16(6): e1900052, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946516

RESUMO

One new racemic mixture, penicilliode A (1) and four pairs of enantiomeric polyketides, penicilliode B and C (2 and 3) and coniochaetone B and C (4 and 5), were obtained from the starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2. Interestingly, the strain GGF16-1-2 can produce enantiomers. The absolute configuration of 1 was determined by X-ray diffraction (XRD) analysis, and the absolute configurations of 2-4 were determined by the optical rotation (OR) values and electronic circular dichroism (ECD) calculations. Compounds 1-5 were firstly isolated from the marine-derived fungus Penicillium as racemates, and 2-5 were separated by HPLC with a chiral stationary phase. All the compounds were evaluated for their antibacterial, cytotoxic and inhibitory activities against PDE4D2.


Assuntos
Penicillium/metabolismo , Policetídeos/química , Estrelas-do-Mar/microbiologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Conformação Molecular , Penicillium/química , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Estereoisomerismo , Simbiose
3.
Anal Chem ; 91(9): 6329-6339, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-30978003

RESUMO

In a clinical assay, enzymes are essential biomarkers for human disease diagnosis. In this work, a spectral-resolved single-particle detection (SPD) method is introduced to quantify alkaline phosphatase (ALP) activity in human serum with a supraparticle (SP) based on MnO2-modified gold nanoparticle (denoted as GNP@MnO2 SP) as the probe. In the presence of ALP, 2-phospho-l-ascorbic acid trisodium salt can be hydrolyzed into l-ascorbic acid, which serves as a good reduction agent to trigger the decomposition of the MnO2 shell on the GNP surface. Given that a trace amount of ALP exists, noticeable scattering color change can be detected at the single-particle level due to the sensitive localized surface plasmon resonance (LSPR) effect from GNPs. With spectral-resolved dark-field optical microscopy, a linear dynamic range of 0.06 to 2.48 mU/mL ( R2 = 0.99) and a very low limit of detection of 5.8 µU/mL for the ALP assay are readily achieved, which is more sensitive over the methods based on ensemble sample measurement. As a consequence, this strategy opens a new avenue for the design of an ultrasensitive detection method for disease-correlated biomarker diagnosis in the future.

4.
J Med Chem ; 62(8): 4218-4224, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30916555

RESUMO

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.

5.
J Med Chem ; 62(7): 3707-3721, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30888810

RESUMO

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.

6.
J Med Chem ; 62(4): 2099-2111, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30689375

RESUMO

Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC50 = 0.87 nM, ∼2000-fold improvement in potency) with cocrystal confirmation.

7.
ACS Chem Neurosci ; 10(1): 537-551, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30252439

RESUMO

A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 µM; PDE9A: IC50 = 0.530 µM) and 11b (AChE: IC50 = 0.223 µM; PDE9A: IC50 = 0.285 µM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Aß25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.

8.
Bioorg Med Chem ; 26(22): 5934-5943, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429100

RESUMO

AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 µM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Nitrilos/farmacologia , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
9.
Acta Pharm Sin B ; 8(4): 615-628, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30109185

RESUMO

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC50 values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound 11a, the most effective one, gave the IC50 of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure-activity relationships and provide evidence for further structural modifications.

10.
J Med Chem ; 61(18): 8468-8473, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30148362

RESUMO

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.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Microssomos Hepáticos/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Administração Oral , Animais , Cristalografia por Raios X , Canal de Potássio ERG1/antagonistas & inibidores , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 5/química , Conformação Proteica , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Relação Estrutura-Atividade
11.
Front Chem ; 6: 167, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868568

RESUMO

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 µM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

12.
CNS Neurosci Ther ; 24(10): 889-896, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29722134

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. METHODS: We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. RESULTS: C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. CONCLUSION: Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.


Assuntos
Corticosterona/toxicidade , GMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Transformada , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Elevação dos Membros Posteriores/psicologia , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Restrição Física/efeitos adversos , Natação/psicologia
13.
Org Lett ; 20(7): 1712-1715, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518327

RESUMO

A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D2O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation.

14.
J Med Chem ; 61(13): 5467-5483, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29363967

RESUMO

Alzheimer's disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme family responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also reviewed and discussed.


Assuntos
Doença de Alzheimer/fisiopatologia , Cognição/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Humanos , Inibidores de Fosfodiesterase/uso terapêutico
15.
Bioorg Med Chem ; 26(1): 119-133, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174506

RESUMO

Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ±â€¯0.67 µM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ±â€¯0.04 µM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5'-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Descoberta de Drogas , Nucleosídeos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Purinas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
16.
J Enzyme Inhib Med Chem ; 33(1): 260-270, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29271265

RESUMO

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Antioxidantes/farmacologia , Descoberta de Drogas , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Relação Estrutura-Atividade
17.
J Mol Model ; 23(9): 272, 2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-28861624

RESUMO

Recently, a series of xanthone analogues has been identified as α-glucosidase inhibitors. To provide deeper insight into the three-dimensional (3D) structural requirements for the activities of these molecules, CoMFA and CoMSIA approaches were employed on 54 xanthones to construct 3D-QSAR models. Their bioactive conformations were first investigated by docking studies and optimized by subsequent molecular dynamics (MD) simulations using the homology modeled structure of the target protein. Based on the docking/MD-determined conformers, 3D-QSAR studies generated several significant models in terms of 47 molecules as the training set. The best model (CoMSIA-SHA) yielded q 2 of 0.713, r 2 of 0.967 and F of 140.250. The robustness of the model was further externally confirmed by a test set of the remaining molecules (q 2 = 0.793, r 2 = 0.902, and k = 0.905). Contour maps provided much information for future design and optimization of new compounds with high inhibitory activities towards α-glucosidase. Graphical Abstract CoMSIA/SHA contour map of xanthone α-glucosidase inhibitor.


Assuntos
Glicosídeo Hidrolases/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Saccharomyces cerevisiae/enzimologia , Xantonas/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Xantonas/química , Xantonas/metabolismo
18.
ACS Chem Neurosci ; 8(11): 2522-2534, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28783948

RESUMO

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Pirazolonas/farmacologia , Pirimidinonas/farmacologia , Rivastigmina/farmacologia , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/química , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Estresse Oxidativo , Fragmentos de Peptídeos/química , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Pirazolonas/síntese química , Pirazolonas/química , Pirimidinonas/síntese química , Pirimidinonas/química , Rivastigmina/síntese química , Rivastigmina/química
19.
J Med Chem ; 60(15): 6622-6637, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28686445

RESUMO

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.


Assuntos
Cromonas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirróis/uso terapêutico , Animais , Células CHO , Domínio Catalítico , Cromonas/administração & dosagem , Cromonas/síntese química , Cromonas/farmacocinética , Cricetulus , Inibidores do Citocromo P-450 CYP1A2/administração & dosagem , Inibidores do Citocromo P-450 CYP1A2/síntese química , Inibidores do Citocromo P-450 CYP1A2/farmacocinética , Inibidores do Citocromo P-450 CYP1A2/uso terapêutico , Estabilidade de Medicamentos , Canal de Potássio ERG1/antagonistas & inibidores , Feminino , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/farmacocinética , Pirróis/administração & dosagem , Pirróis/síntese química , Pirróis/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Citrato de Sildenafila/farmacologia , Relação Estrutura-Atividade
20.
Acta Pharmacol Sin ; 38(9): 1257-1268, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28649129

RESUMO

Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 µmol/L) or ISO (1 µmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 µmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg-1·d-1, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Cardiomegalia/tratamento farmacológico , GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
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