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1.
Acta Pharmacol Sin ; 44(1): 221-233, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35676531

RESUMO

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.


Assuntos
Inibidores da Fosfodiesterase 5 , Hipertensão Arterial Pulmonar , Humanos , Masculino , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirimidinonas , Biotransformação , Fezes , Administração Oral
2.
Acta Pharmacol Sin ; 43(12): 3130-3138, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35296780

RESUMO

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.


Assuntos
COVID-19 , Nucleosídeos , Humanos , SARS-CoV-2 , Voluntários Saudáveis , Método Duplo-Cego , Área Sob a Curva , China , Administração Oral , Relação Dose-Resposta a Droga
3.
J Nat Prod ; 82(11): 3065-3073, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31718182

RESUMO

Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 µM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 µM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 µM) than hederagenin (IC50 > 20 µM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 µM) and osimertinib-resistant H1975-LTC (IC50 7.6 µM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Ácido Oleanólico/análogos & derivados , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Humanos , Mutação , Óxido Nítrico/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Inibidores de Proteínas Quinases/química
4.
J Org Chem ; 80(16): 8183-8, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26246028

RESUMO

A novel and efficient strategy for the synthesis of sterically hindered 4-amino-3-acyl-2-naphthols through a palladium-catalyzed coupling reaction involving isocyanide chemselective insertion and domino isomerization has been developed. The methodology, which is in accordance with the principle of "atom and step economy", efficiently constructs 4-amino-3-acyl-2-naphthols in moderate to good yields.


Assuntos
Cianetos/química , Naftóis/síntese química , Paládio/química , Catálise , Isomerismo , Estrutura Molecular
5.
J Asian Nat Prod Res ; 15(1): 53-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23323550

RESUMO

A new polyoxygenated cyclohexene bonianol A (1) and another new polyoxygenated seco-cyclohexene bonianol B (2) were isolated from the leaves of Uvaria boniana, and their structures were established on the basis of spectroscopic methods including IR, HR-ESI-MS, 1D, and 2D NMR.


Assuntos
Cicloexenos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Oxigênio/química , Uvaria/química , Cicloexenos/química , Cicloexenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células HL-60 , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química
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