RESUMO
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.
Assuntos
Anabolizantes/química , Pirimidinonas/química , Receptores de Detecção de Cálcio/antagonistas & inibidores , Administração Oral , Anabolizantes/administração & dosagem , Anabolizantes/farmacocinética , Animais , Masculino , Hormônio Paratireóideo/metabolismo , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Detecção de Cálcio/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Conformação Molecular , Estrutura Molecular , Osteoporose/tratamento farmacológico , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
[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.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Diterpenos/síntese química , Ciclização , Estrutura MolecularRESUMO
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.
Assuntos
Serviços Contratados/organização & administração , Indústria Farmacêutica/organização & administração , Pesquisa/organização & administração , Química Farmacêutica/métodos , Comunicação , Serviços Contratados/normas , Desenho de Fármacos , Descoberta de Drogas/métodos , Indústria Farmacêutica/normas , Eficiência Organizacional , Humanos , Melhoria de Qualidade , Pesquisa/normas , Fluxo de TrabalhoRESUMO
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.
Assuntos
Receptores CXCR4/química , Animais , Linhagem Celular , Quimiocina CXCL12 , Cristalografia por Raios X , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Proteínas de Membrana , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Proteínas Recombinantes/química , Spodoptera , Tioureia/análogos & derivados , Tioureia/químicaRESUMO
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.