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1.
J Med Chem ; 63(7): 3485-3507, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196340

RESUMO

Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound 1 resulted in being a potent TbrPDEB1 inhibitor with interesting activity against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and T. brucei. Compound 14 presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Ftalazinas/farmacologia , Tripanossomicidas/farmacologia , Animais , Cristalografia por Raios X , Estabilidade de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Ftalazinas/síntese química , Ftalazinas/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos
2.
Front Chem ; 8: 608030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33553105

RESUMO

Several members of the 3',5'-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 µM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.

3.
Bioorg Med Chem ; 27(18): 4013-4029, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378593

RESUMO

Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/efeitos dos fármacos , Inibidores de Fosfodiesterase/uso terapêutico , Proteínas de Protozoários/efeitos dos fármacos , Humanos , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 27(18): 3998-4012, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31327675

RESUMO

Several 3',5'-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.


Assuntos
Inibidores de Fosfodiesterase/uso terapêutico , Trypanosoma brucei brucei/efeitos dos fármacos , Humanos , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade
5.
Cell Rep ; 8(6): 1649-1658, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25242326

RESUMO

Functional biomolecules, including small noncoding RNAs (ncRNAs), are released and transmitted between mammalian cells via extracellular vesicles (EVs), including endosome-derived exosomes. The small RNA composition in cells differs from exosomes, but underlying mechanisms have not been established. We generated small RNA profiles by RNA sequencing (RNA-seq) from a panel of human B cells and their secreted exosomes. A comprehensive bioinformatics and statistical analysis revealed nonrandomly distributed subsets of microRNA (miRNA) species between B cells and exosomes. Unexpectedly, 3' end adenylated miRNAs are relatively enriched in cells, whereas 3' end uridylated isoforms appear overrepresented in exosomes, as validated in naturally occurring EVs isolated from human urine samples. Collectively, our findings suggest that posttranscriptional modifications, notably 3' end adenylation and uridylation, exert opposing effects that may contribute, at least in part, to direct ncRNA sorting into EVs.


Assuntos
Exossomos/metabolismo , RNA não Traduzido/metabolismo , Adenosina/química , Adenosina/metabolismo , Linfócitos B/metabolismo , Biologia Computacional , Herpesvirus Humano 4/genética , Humanos , MicroRNAs/metabolismo , Análise de Sequência de RNA , Uridina/química , Uridina/metabolismo
6.
Mol Pharmacol ; 77(5): 734-43, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20103609

RESUMO

The histamine H(4) receptor (H(4)R) is the latest identified histamine receptor to emerge as a potential drug target for inflammatory diseases. Animal models are employed to validate this potential drug target. Concomitantly, various H(4)R orthologs have been cloned, including the human, mouse, rat, guinea pig, monkey, pig, and dog H(4)Rs. In this article, we expressed all these H(4)R orthologs in human embryonic kidney 293T cells and compared their interactions with currently used standard H(4)R ligands, including the H(4)R agonists histamine, 4-methylhistamine, guanidinylethyl isothiourea (VUF 8430), the H(4)R antagonists 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) and [(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine (VUF 6002), and the inverse H(4)R agonist thioperamide. Most of the evaluated ligands display significantly different affinities at the different H(4)R orthologs. These "natural mutants" of H(4)R were used to study ligand-receptor interactions by using chimeric human-pig-human and pig-human-pig H(4)R proteins and site-directed mutagenesis. Our results are a useful reference for ligand selection for studies in animal models of diseases and offer new insights in the understanding of H(4)R-ligand receptor interactions.


Assuntos
Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/genética , Sequência de Aminoácidos , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , DNA Complementar/genética , Cães , Variação Genética , Cobaias , Haplorrinos , Histamina/metabolismo , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Plasmídeos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H4 , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Transfecção
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