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1.
ACS Med Chem Lett ; 15(5): 646-652, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38746889

RESUMO

The potassium (K+) ion channel KCNK13 is specifically expressed in human microglia with elevated expression observed in post-mortem human brain tissue from patients with Alzheimer's disease. Modulation of KCNK13 activity by a small-molecule inhibitor is proposed as a potential treatment for neurodegenerative diseases. Herein, we describe the evolution of a series of KCNK13 inhibitors derived from a high-throughput screening campaign, resulting in CVN293, a potent, selective, and brain permeable clinical candidate molecule. CVN293 demonstrated a concentration-dependent inhibition of the NLRP3-inflammasome mediated production of IL-1ß from LPS-primed murine microglia. Cross-species pharmacokinetic data of CVN293 are also disclosed. These findings support the advancement of CVN293 in clinical trials.

2.
J Med Chem ; 66(18): 12858-12876, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37708305

RESUMO

From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited ß-arrestin signaling and receptor desensitization, indicating biased signaling. A compound that showed minimal GPR55 desensitization demonstrated a reduction in firing frequency of medium spiny neurons cultured from rat striatum but did not reverse motor deficits in a rat hypolocomotion model. Further profiling of several desensitizing and non-desensitizing lead compounds showed that they are selective over related cannabinoid receptors CB1 and CB2 and that unbound brain concentrations well above the respective GPR55 EC50 can be readily achieved following oral administration. The novel brain-penetrant GPR55 agonists disclosed can be used to probe the role of this receptor in the brain.


Assuntos
Agonistas de Receptores de Canabinoides , Transdução de Sinais , Humanos , Ratos , Animais , Receptores de Canabinoides , beta-Arrestinas , Corpo Estriado/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptor CB2 de Canabinoide , Receptor CB1 de Canabinoide
3.
J Med Chem ; 66(17): 11718-11731, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37651656

RESUMO

Nicotinic acetylcholine receptor (nAChR) α6 subunit RNA expression is relatively restricted to midbrain regions and is located presynaptically on dopaminergic neurons projecting to the striatum. This subunit modulates dopamine neurotransmission and may have therapeutic potential in movement disorders. We aimed to develop potent and selective α6-containing nAChR antagonists to explore modulation of dopamine release and regulation of motor function in vivo. High-throughput screening (HTS) identified novel α6-containing nAChR antagonists and led to the development of CVN417. This molecule blocks α6-containing nAChR activity in recombinant cells and reduces firing frequency of noradrenergic neurons in the rodent locus coeruleus. CVN417 modulated phasic dopaminergic neurotransmission in an impulse-dependent manner. In a rodent model of resting tremor, CVN417 attenuated this behavioral phenotype. These data suggest that selective antagonism of α6-containing nAChR, with molecules such as CVN417, may have therapeutic utility in treating the movement dysfunctions observed in conditions such as Parkinson's disease.


Assuntos
Dopamina , Receptores Nicotínicos , Encéfalo , Membrana Celular , Corpo Estriado , Antagonistas Nicotínicos/farmacologia
4.
Bioorg Med Chem Lett ; 27(11): 2594-2601, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28400234

RESUMO

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.


Assuntos
Imidazóis/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Administração Oral , Animais , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Cobaias , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Concentração Inibidora 50 , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
5.
Mol Imaging Biol ; 18(1): 52-61, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26084246

RESUMO

PURPOSE: The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery. PROCEDURES: Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging. RESULTS: ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M(-1) cm(-1), emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system. CONCLUSIONS: Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica/métodos , Fenômenos Ópticos , Cirurgia Assistida por Computador/métodos , Animais , Morte Celular , Linhagem Celular Tumoral , Feminino , Fluorescência , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Cuidados Intraoperatórios , Camundongos Nus , Espectroscopia de Luz Próxima ao Infravermelho , Sus scrofa , Distribuição Tecidual
6.
J Med Chem ; 58(6): 2845-54, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25711712

RESUMO

The success of near-infrared (NIR) fluorescence to be employed for intraoperative imaging relies on the ability to develop a highly stable, NIR fluorescent, nontoxic, biocompatible, and highly excreted compound that retains a reactive functionality for conjugation to a cancer-recognizing peptide. Herein, systematic modifications to previously detailed fluorophore ZW800-1 are explored. Specific modifications, including the isosteric replacement of the O atom of ZW800-1, include nucleophilic amine and sulfur species attached to the heptamethine core. These novel compounds have shown similar satisfactory results in biodistribution and clearance while also expressing increased stability in serum. Most importantly, all of the synthesized and evaluated compounds display a reactive functionality (either a free amino group or carboxylic acid moiety) for further bioconjugation. The results obtained from the newly prepared derivatives demonstrate that the central substitution with the studied linking agents retains the ultralow background in vivo performance of the fluorophores regardless of the total net charge.


Assuntos
Meios de Contraste/análise , Corantes Fluorescentes/análise , Imagem Óptica , Compostos de Amônio Quaternário/análise , Ácidos Sulfônicos/análise , Cirurgia Assistida por Computador , Animais , Simulação por Computador , Meios de Contraste/farmacocinética , Corantes Fluorescentes/farmacocinética , Raios Infravermelhos , Masculino , Camundongos , Modelos Moleculares , Neoplasias/cirurgia , Imagem Óptica/métodos , Compostos de Amônio Quaternário/farmacocinética , Ácidos Sulfônicos/farmacocinética , Cirurgia Assistida por Computador/métodos
7.
RSC Adv ; 4(102): 58762-58768, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25530846

RESUMO

Functional near-infrared (NIR) fluorophores have played a major role in the recent advances in bioimaging. However, the optical and physicochemical stabilities of NIR fluorophores in the biological and physiological environment are still a challenge. Especially, the ether linkage on the meso carbon of heptamethine core is fragile when exposed to serum proteins or other amine-rich biomolecules. To solve such a structural limitation, a rigid carbon-carbon bond was installed onto the framework of ether-linked NIR fluorophores through the Suzuki coupling. The robust fluorophores replaced as ZW800-1C and ZW800-3C displayed enhanced optical and chemical stability in various solvents and a 100% warm serum environment (> 99%, 24 h). The biodistribution and clearance of C-C coupled ZW800 compounds were almost identical to the previously developed oxygen-substituted ZW800 compounds. When conjugated with a small molecule ligand, ZW800-1C maintained the identical stable form in warm serum (>98%, 24 h), while ZW800-1A hydrolyzed quickly after 4 h incubation (34%, 24 h).

8.
Biochem Pharmacol ; 92(2): 192-205, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25124704

RESUMO

Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Microtúbulos/efeitos dos fármacos , Noscapina/análogos & derivados , Moduladores de Tubulina/farmacologia , Água/química , Animais , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Cabras , Inibidores do Crescimento/química , Células HeLa , Humanos , Masculino , Camundongos , Microtúbulos/fisiologia , Noscapina/farmacologia , Estrutura Secundária de Proteína , Solubilidade , Moduladores de Tubulina/química
9.
Bioorg Med Chem Lett ; 23(24): 6747-54, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24231362

RESUMO

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.


Assuntos
Imidazóis/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Tiazóis/química , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêutico
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