RESUMEN
BACKGROUND: Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis. OBJECTIVE: We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics. METHODS: We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated. RESULTS: TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers. CONCLUSION: We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.
Asunto(s)
Antiinflamatorios/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Piel/efectos de los fármacos , Administración Tópica , Adulto , Anciano , Betametasona/análogos & derivados , Betametasona/uso terapéutico , Biomarcadores/metabolismo , Diferenciación Celular , Clobetasol/uso terapéutico , Citocinas/metabolismo , Femenino , Humanos , Hiperplasia , Masculino , Persona de Mediana Edad , Efecto Placebo , Psoriasis/tratamiento farmacológico , Piel/patología , Tacrolimus/análogos & derivados , Tacrolimus/uso terapéutico , Adulto JovenRESUMEN
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacocinética , Área Bajo la Curva , Modelos Animales de Enfermedad , Hepacivirus/fisiología , Hepatitis C/virología , Ratones , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacologíaRESUMEN
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacología , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Conformación Molecular , Datos de Secuencia Molecular , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Descubrimiento de Drogas , Urea/química , Urea/farmacología , Fármacos Anti-VIH/química , VIH-1/efectos de los fármacosRESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Asunto(s)
Isoxazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Isoxazoles/química , Isoxazoles/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Colestasis/tratamiento farmacológico , Proteínas de Unión al ADN/agonistas , Isoxazoles/síntesis química , Isoxazoles/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/química , Colestasis/metabolismo , Colestasis/patología , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Modelos Animales de Enfermedad , Perros , Mucosa Gástrica/metabolismo , Haplorrinos , Isoxazoles/química , Ratones , Conformación Molecular , Estructura Molecular , Naftalenos/química , Ratas , Receptores Citoplasmáticos y Nucleares/química , Estómago/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl(3)) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.
Asunto(s)
Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/farmacocinética , Organofosfatos/farmacología , Organofosfatos/farmacocinética , Profármacos/farmacología , Profármacos/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/farmacocinética , Animales , Disponibilidad Biológica , Biotransformación , Células CACO-2 , Carbamatos , Perros , Furanos , Humanos , Concentración de Iones de Hidrógeno , Absorción Intestinal , Masculino , Espectrometría de Masas , Organofosfatos/toxicidad , Profármacos/toxicidad , Ratas , Ratas Wistar , Sulfonamidas/toxicidadRESUMEN
The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.