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1.
Inflammopharmacology ; 30(3): 1063-1077, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35352233

RESUMEN

BACKGROUND: A meta-analysis of randomized controlled trials (RCTs) was conducted to systematically evaluate the effects of berberine on the inflammatory markers of metabolic syndrome (MetS) and related disorders. METHOD: Databases that were searched from inception to October 2020 included PubMed, Web of Science, the Cochrane Library, CNKI, VIP, WanFang Data, and ClinicalTrials.gov. Two reviewers independently selected articles and extracted data. The pooled evaluations were entered and analyzed in Review Manager 5.3. RESULTS: Of the 7387 publications screened, 52 studies were included, and the related trials involved 4616 patients. Pooled estimates showed that the use of berberine could significantly reduce the concentration level of C-reactive protein (CRP) [standardized mean difference (SMD) = - 1.54, 95% confidence intervals (CI) - 1.86, - 1.22, p < 0.05], tumor necrosis factor-α (TNF-α) [SMD = - 1.02, 95% CI - 1.27, - 0.77, p < 0.05], and interleukin 6 (IL-6) [SMD = - 1.17, 95% CI - 1.53, - 0.81, p < 0.05] among patients with MetS and related disorders. However, it did not affect the level of interleukin 1ß (IL-1ß) [SMD = - 0.81, 95% CI - 1.80, 0.17, p = 0.11]. CONCLUSION: Overall, the use of berberine in patients with MetS and related disorders appeared to significantly decrease several inflammatory markers. Further multi-center and rigorous investigations with larger patient populations are encouraged to confirm the effect of berberine on MetS and related disorders.


Asunto(s)
Berberina , Síndrome Metabólico , Berberina/uso terapéutico , Biomarcadores/sangre , Proteína C-Reactiva/análisis , China , Citocinas/sangre , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
2.
Pharmacoeconomics ; 41(3): 295-306, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36658308

RESUMEN

BACKGROUND: The disutilities of adverse events (AEs) are important inputs for cost-utility analysis (CUA), reflecting the impacts of AEs on health outcomes. Health technology assessment institutions and scholars have proposed recommendations for applying disutility values in economic evaluations. OBJECTIVES: This study aimed to identify the current use of disutilities of AEs as model parameters in the CUA of cancer drug therapy and to compare the discrepancies between the use of disutilities and published recommendations. METHODS: A systematic search was conducted on the PubMed, Web of Science, and Cochrane Library databases, as well as the official websites of the National Institute for Health and Care Research (NIHR), the Institute for Clinical and Economic Review (ICER), the Institute for Quality and Efficiency in Health Care (IQWiG), the Canadian Agency for Drugs and Technologies in Health (CADTH), and the Centre for Reviews and Dissemination (CRD) for CUAs of drug therapy for cancer published in English from January 2019 to April 2022. Information about the use of disutilities of AEs (whether and how disutilities were used, or why they were not used) in selected studies was extracted and compared with published recommendations. Descriptive analyses were used to summarize the results. RESULTS: A total of 467 CUAs were included, 54% (254/467) of which included disutilities of AEs in their model. The proportion that included these disutilities increased from 2019 to 2021, ranging from 47% (51/107) to 61% (116/190). Only 6% (15/254) of the CUAs using disutilities of AEs considered all five recommendations about the justification for inclusion and exclusion, description of values and sources, grades of AEs, calculation, and uncertainty analyses. Only 15% (72/467) provided a clear justification for inclusion and exclusion of disutilities of AEs, and 7% (17/254) did not provide values or sources. In total, 69% (175/254) of the analyses focused on AEs of grade 3 or greater, and 11% (28/254) applied utility decrements for grades 1 and 2. Disutilities of AEs were generally calculated using the incidence rates, which were clearly stated in 49% (65/132) of the analyses. Uncertainty analyses were conducted in 84% (214/254) of the CUAs. CONCLUSIONS: The current use of disutilities of AEs in CUAs shows some discrepancies with recommendations proposed in the literature. One is that detailed information about the use of disutilities of AEs was not reported and the other is that essential methods to analyze the impact of AEs on quality-adjusted life-years were not thoroughly conducted. Therefore, it is suggested that researchers should attach importance to the impact of AEs on health-related quality of life. Furthermore, an application process was developed for the disutilities of AEs to remind and guide researchers to correctly use the disutilities of AEs as parameters in the decision-analytic model.


Asunto(s)
Neoplasias , Calidad de Vida , Humanos , Análisis Costo-Beneficio , Canadá , Neoplasias/tratamiento farmacológico
3.
Bioorg Med Chem Lett ; 21(11): 3390-4, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21514824

RESUMEN

The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.


Asunto(s)
Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Propionatos/síntesis química , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Ciclización , Modelos Animales de Enfermedad , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Propionatos/química , Propionatos/farmacocinética
4.
Bioorg Med Chem Lett ; 21(6): 1865-70, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21353541

RESUMEN

A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.


Asunto(s)
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacología , Pirrolidinas/química , Receptores Adrenérgicos beta 3/efectos de los fármacos , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Modelos Moleculares
5.
J Org Chem ; 75(5): 1733-9, 2010 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-20141223

RESUMEN

Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.


Asunto(s)
Hidrocarburos Halogenados/química , Imidazoles/síntesis química , Oxazoles/síntesis química , Tiazoles/síntesis química , Catálisis , Reactivos de Enlaces Cruzados/química , Imidazoles/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Oxazoles/química , Paladio , Estereoisomerismo , Tiazoles/química
7.
Nanoscale ; 11(14): 6766-6775, 2019 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-30907895

RESUMEN

Rechargeable battery systems, including Li-ion batteries and Na-ion batteries, have attracted great interest in energy storage because of their high energy density, low cost, efficient energy storage and suitable redox potential. Nevertheless, their rapid development is still greatly hampered by some typical constraints including low coulombic efficiency, large volume changes and severe particle agglomeration and pulverization during the charge-discharge process. Here, we fabricate a few-layer MoSe2 confined within a ZnSe-C hollow porous sphere nanocomposite through a simple self-assembly strategy followed by selenization, which efficiently circumvents these problems. The fabricated ZnSe/MoSe2@C electrode demonstrates diverse advantages, including the existence of a few-layer structure, an in situ porous carbon matrix, multicomponent coordination and excellent pseudocapacitive behavior. When used as an anode material, it displays extraordinarily attractive electrochemical performance for both lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). The reversible capacity of ZnSe/MoSe2@C for LIBs reaches as high as 1051 mA h g-1 at 0.2 A g-1 (150 cycles). A long-term high-rate cycling test reveals an excellent stability of 524 mA h g-1 at 4 A g-1 after 600 cycles. In addition, for SIBs, ZnSe/MoSe2@C also manifests a high initial coulombic efficiency of 89% at 0.2 A g-1 and a remarkable reversible capacity of 381 mA h g-1 at a high current density of 4 A g-1 even after 250 cycles with negligible capacity loss. This is one of the best performances of ZnSe-based anode materials for SIBs reported so far. The regulation strategy reported in the present work is expected to offer new insights into the fabrication of high performance anode materials for SIBs.

8.
ACS Med Chem Lett ; 9(11): 1082-1087, 2018 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-30429949

RESUMEN

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.

9.
J Med Chem ; 50(18): 4295-303, 2007 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-17691760

RESUMEN

The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.


Asunto(s)
Neoplasias/diagnóstico por imagen , Compuestos de Organotecnecio/aislamiento & purificación , Radiofármacos/aislamiento & purificación , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Animales , Línea Celular Tumoral , Dicroismo Circular , Femenino , Marcaje Isotópico , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/metabolismo , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Neoplasias Pancreáticas , Ensayo de Unión Radioligante , Cintigrafía , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Somatostatina/química , Somatostatina/aislamiento & purificación , Somatostatina/farmacocinética , Estereoisomerismo , Distribución Tisular
10.
J Med Chem ; 49(12): 3614-27, 2006 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-16759103

RESUMEN

A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/síntesis química , Fenilalanina/análogos & derivados , Inhibidores de Proteasas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Canales de Calcio Tipo L/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Proteínas Musculares/antagonistas & inhibidores , Músculo Esquelético/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5 , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Conejos , Canales de Sodio , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología
11.
J Med Chem ; 57(8): 3205-12, 2014 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-24660890

RESUMEN

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Hipoglucemiantes/farmacología , Piranos/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/toxicidad , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/toxicidad , Piranos/síntesis química , Piranos/farmacocinética , Piranos/toxicidad , Relación Estructura-Actividad
12.
Org Lett ; 12(16): 3578-81, 2010 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-20704397

RESUMEN

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.


Asunto(s)
Hidrocarburos Bromados/química , Hidrocarburos Clorados/química , Mesilatos/química , Oxazoles/química , Paladio/química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Oxazoles/síntesis química , Estereoisomerismo
13.
Bioorg Med Chem Lett ; 15(10): 2533-6, 2005 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-15863311

RESUMEN

anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. These are among the most potent compounds reported to date lacking an electrophilic trap. The most potent compound among these is 5-oxo-1,2,4-oxadiazole 44, which is a 3 nM DPP-IV inhibitor.


Asunto(s)
Dipeptidil Peptidasa 4/efectos de los fármacos , Fenilalanina/farmacología , Inhibidores de Proteasas/farmacología , Fenilalanina/química , Inhibidores de Proteasas/química
14.
Bioorg Med Chem Lett ; 14(5): 1265-8, 2004 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-14980678

RESUMEN

Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice.


Asunto(s)
Inhibidores de la Adenosina Desaminasa , Amidas/química , Glicoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Pirrolidinas/química , Adenosina Desaminasa/metabolismo , Amidas/farmacología , Animales , Perros , Flúor/química , Flúor/farmacología , Glicoproteínas/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteasas/farmacología , Pirrolidinas/farmacología , Ratas
15.
Bioorg Med Chem Lett ; 14(18): 4763-6, 2004 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-15324904

RESUMEN

Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Piperazinas/farmacología , Inhibidores de Proteasas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad
16.
Bioorg Med Chem Lett ; 14(1): 43-6, 2004 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-14684294

RESUMEN

Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Glicina/análogos & derivados , Glicina/metabolismo , Canales de Potasio con Entrada de Voltaje , Inhibidores de Proteasas/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Canales de Potasio Éter-A-Go-Go , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacocinética , Ratones , Canales de Potasio/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas
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