RESUMEN
Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.
Asunto(s)
Anabolizantes/química , Pirimidinonas/química , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Anabolizantes/administración & dosificación , Anabolizantes/farmacocinética , Animales , Masculino , Hormona Paratiroidea/metabolismo , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Asunto(s)
Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Humanos , Conformación Molecular , Estructura Molecular , Osteoporosis/tratamiento farmacológico , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
[Structure: see text] 12-hydroxydaphnetoxins, members of the structurally fascinating daphnane diterpene family, exhibit a wide range of significant biological activities. A general route to the BC-ring system of 12-hydroxy daphnetoxins is reported based on D-ribose. Depending on the choice of protecting groups and solvent, the oxidopyrylium-alkene [5+2] cycloaddition originating from A provides cycloadduct diastereomer B or C with good to excellent selectivity.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Diterpenos/síntesis química , Ciclización , Estructura MolecularRESUMEN
Confronted with the need to significantly raise the productivity of remotely located chemistry CROs Pfizer embraced a commitment to continuous improvement which leveraged the tools from both Lean Six Sigma and queue management theory to deliver positive measurable outcomes. During 2012 cycle times were reduced by 48% by optimization of the work in progress and conducting a detailed workflow analysis to identify and address pinch points. Compound flow was increased by 29% by optimizing the request process and de-risking the chemistry. Underpinning both achievements was the development of close working relationships and productive communications between Pfizer and CRO chemists.
Asunto(s)
Servicios Contratados/organización & administración , Industria Farmacéutica/organización & administración , Investigación/organización & administración , Química Farmacéutica/métodos , Comunicación , Servicios Contratados/normas , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Industria Farmacéutica/normas , Eficiencia Organizacional , Humanos , Mejoramiento de la Calidad , Investigación/normas , Flujo de TrabajoRESUMEN
Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.
Asunto(s)
Receptores CXCR4/química , Animales , Línea Celular , Quimiocina CXCL12 , Cristalografía por Rayos X , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Proteínas de la Membrana , Modelos Moleculares , Unión Proteica , Conformación Proteica , Multimerización de Proteína , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Proteínas Recombinantes/química , Spodoptera , Tiourea/análogos & derivados , Tiourea/químicaRESUMEN
Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.