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1.
Antimicrob Agents Chemother ; 67(1): e0112322, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36507677

RESUMO

A phase 1b, randomized, placebo-controlled, double-blind, multiple ascending dose study (NCT02858973) was conducted to assess the safety, tolerability, and pharmacokinetics of the new antituberculosis agent telacebec (Q203). A total of 47 healthy adult subjects entered the study; 36 received telacebec, and 11 received placebo. Telacebec at doses of 20, 50, 100, 160, 250, and 320 mg was orally administered once daily with a standard meal for 14 days. Multiple oral doses of telacebec up to 320 mg daily for 14 days appeared to be safe and well tolerated by healthy adult subjects in this study. There were no deaths, serious adverse events, or subject discontinuations due to adverse events. Following oral doses of telacebec, the overall extent (AUCτ) and peak (Cmax) exposures of telacebec increased from 538.94 to 10,098.47 ng·h/mL and from 76.43 to 1502.33 ng/mL, respectively, with increasing telacebec doses from 20 mg to 320 mg. A steady state was achieved for plasma telacebec by day 12, and there was 1.9- to 3.1-fold accumulation in the extent of telacebec exposure after daily doses for 14 days. Analysis of plasma samples from the participants indicated that telacebec was the primary circulating entity with no significant metabolites. Three potential metabolites of telacebec have been identified, which may be relatively minimal compared to the parent drug. Consistent with findings from preclinical and previous single-dose clinical studies, these results also support the potential of telacebec for further development as a safe and effective agent for the treatment of tuberculosis.


Assuntos
Tuberculose , Adulto , Humanos , Área Sob a Curva , Tuberculose/tratamento farmacológico , Método Duplo-Cego , Relação Dose-Resposta a Droga , Administração Oral
2.
Antimicrob Agents Chemother ; 66(1): e0143621, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34694872

RESUMO

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 to 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 to 800 mg), telacebec plasma concentration reached the maximal plasma concentration (Cmax) in average 2.0 to 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration versus time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for Cmax. Moderate delay in Tmax (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support further investigation of telacebec for the treatment of tuberculosis.


Assuntos
Piperidinas , Piridinas , Administração Oral , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Imidazóis , Masculino
3.
Cancers (Basel) ; 14(19)2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36230744

RESUMO

Although immune checkpoint blockade (ICB) represents a major breakthrough in cancer immunotherapy, only a limited number of patients with cancer benefit from ICB-based immunotherapy because most immune checkpoint inhibitors (ICIs) target only T cell activation. Therefore, targeting non-T cell components in the tumor microenvironment (TME) can help subvert resistance and increase the applications of ICB-based therapy. Axl and Mer are involved in the carcinogenesis of multiple types of cancer by modulating immune and biological behaviors within tumors. Colony stimulating factor 1 receptor (CSF1R) mediates tumorigenesis in the TME by enhancing tumor associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration, facilitating immune escape. Therefore, the simultaneous inhibition of Axl, Mer, and CSF1R kinases may improve therapeutic efficacy by targeting non-T cell components in the TME. Here, we present Q702, a selective, potent small molecule inhibitor targeting Axl, Mer, and CSF1R, for oral administration. Q702 induced antitumor activity in syngeneic tumor mouse models by: remodeling the TME toward immune stimulation; expanding M1 macrophage and CD8 T cell populations and decreasing M2 macrophage and MDSC populations in the TME; and increasing MHC class I and E-cadherin expression in tumor cells. Thus, Q702 may have great potential to broaden the coverage of populations benefiting from ICB-based immunotherapy.

4.
Eur J Med Chem ; 209: 112550, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33268144

RESUMO

Current research suggests therapy-induced senescence (TIS) of cancer cells characterized by distinct morphological and biochemical phenotypic changes represent a novel functional target that may enhance the effectiveness of cancer therapy. In order to identify novel small-molecule inducers of cellular senescence and determine the potential to be used for the treatment of melanoma, a new method of high-throughput screening (HTS) and high-contents screening (HCS) based on the detection of morphological changes was designed. This image-based and whole cell-based technology was applied to screen and select a novel class of antiproliferative agents on cancer cells, 4H-chromeno[2,3-d]pyrimidin-4-one derivatives, which induced senescence-like phenotypic changes in human melanoma A375 cells without serious cytotoxicity against normal cells. To evaluate structure-activity relationship (SAR) study of 4H-chromeno[2,3-d]pyrimidin-4-one scaffold starting from hit 3, a focused library containing diversely modified analogues was constructed and which led to the identification of 38, a novel compound to have remarkable anti-melanoma activity in vitro with good metabolic stability.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Melanoma/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Antineoplásicos/química , Benzopiranos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Melanoma/patologia , Camundongos Endogâmicos BALB C , Pirimidinas/química
5.
Food Chem Toxicol ; 91: 91-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26980244

RESUMO

In the present study, we explore the protective effects of Citrus aurantium L. extract (CAE) against acute and chronic CCl4-induced hepatotoxicity. The quantitative analysis of CAE was performed using HPLC-UV to determine the nobiletin content was approximately 27%. For the acute model, the male ICR mice were orally treated with water, silymarin (positive control, 200 mg/kg) and CAE (50 and 200 mg/kg) for 3 days prior to CCl4 (1 mL/kg, 50% v/v in olive oil) IP injection. For the chronic model (n = 6/group), the mice were treated with each treatment for 28 consecutive days and CCl4 (1 mL/kg, 20%) was injected twice a week. In both the acute and chronic models, the CCl4 alone treated group showed histopathologic alterations with a significantly increase in serum hepatic enzyme levels together with a disrupted anti-oxidative status. In contrast, the CAE treatments restored pathologic alterations and recovered the oxidative status by enhancing antioxidant enzymes and reducing lipid peroxidation levels. Furthermore, CAE enhanced nuclear factor E2-related factor 2 (Nrf2) and its related cytoprotective signals, including NAD(P)H quinone oxidoreductase 1, UDP-glucuronosyltransferase, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrates that CAE exerts a protective effect against CCl4-induced hepatotoxicity with its anti-oxidant, anti-inflammatory, and anti-apoptotic activity.


Assuntos
Intoxicação por Tetracloreto de Carbono/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavonas/farmacologia , Fígado/efeitos dos fármacos , Doença Aguda , Animais , Doença Crônica , Masculino , Camundongos , Camundongos Endogâmicos ICR
6.
J Med Chem ; 57(12): 5293-305, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24870926

RESUMO

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.


Assuntos
Antituberculosos/química , Imidazóis/química , Piridinas/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/síntese química , Piridinas/farmacologia , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
7.
Nat Med ; 19(9): 1157-60, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23913123

RESUMO

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.


Assuntos
Trifosfato de Adenosina/biossíntese , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/farmacologia , Piridinas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Complexo III da Cadeia de Transporte de Elétrons/genética , Imidazóis/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/farmacocinética , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley
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