RESUMEN
A standard protocol was used to determine partition (K) and diffusion (D) coefficients in dermatomed human skin and isolated human skin layers for 50 compounds relevant to cosmetics ingredients. K values were measured in dermatomed skin, isolated dermis, whole epidermis, intact stratum corneum (SC), delipidized SC and SC lipids by direct measurements of the radioactivity in the tissue layers/lipid component vs. buffer samples. D determinations were made in dermatomed skin, isolated dermis, whole epidermis and intact SC using a non-linear regression of the cumulative receptor fluid content of radiolabeled compound, fit to the solution of Fick's 2nd Law. Correlation analysis was completed between K, D, and physicochemical properties. The amount of interindividual (donor) and intraindividual (replicate) variability in the K and D data was characterized for each skin layer and chemical. These data can be further used to help inform the factors that influence skin bioavailability and to help improve in silico models of dermal penetration.
Asunto(s)
Cosméticos/química , Cosméticos/metabolismo , Medición de Riesgo/métodos , Absorción Cutánea , Piel/metabolismo , Adulto , Anciano , Difusión , Femenino , Humanos , Técnicas In Vitro , Lípidos/química , Persona de Mediana Edad , Permeabilidad , Albúmina Sérica BovinaRESUMEN
A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
Asunto(s)
Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Obesidad/tratamiento farmacológico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Fármacos Antiobesidad/química , Disponibilidad Biológica , Dieta , Modelos Animales de Enfermedad , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Conformación Molecular , Piperazinas/química , Ratas , EstereoisomerismoRESUMEN
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed.
Asunto(s)
Piperazinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Perros , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Modelos Moleculares , Piperazinas/química , Relación Estructura-ActividadRESUMEN
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Naftalenos/farmacología , Piperazinas/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Perros , Canal de Potasio ERG1 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Indicadores y Reactivos , Ratones , Naftalenos/síntesis química , Piperazinas/síntesis química , Pérdida de Peso/efectos de los fármacosRESUMEN
The synthesis and biological testing of novel classes of potent melanin-concentrating hormone (MCH-R1) antagonists based on pyrazolopiperazinone and pyrrolopiperazinone scaffolds are described.
Asunto(s)
Piperazinas/síntesis química , Pirazoles/síntesis química , Pirroles/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Células CACO-2 , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Piperazinas/farmacología , Pirazoles/farmacología , Pirroles/farmacología , Ensayo de Unión Radioligante , Receptor de Serotonina 5-HT2C/efectos de los fármacosRESUMEN
The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.