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Background: This Site Feasibility Task Force convened to assess the complex and burdensome process of site feasibility in clinical trials. The objective was to create mutual understanding of challenges and provide suggestions for improving collaboration among sponsors, contract research organizations (CROs), and sites. Methods: The task force was composed of representatives from sponsors, CROs and sites (43 % Sites, 20 % Site Networks, 10 % Small/mid-size sponsors, 10 % Small/mid-size CROs, 10 % Large sponsors, 7 % Large CROs). The group collaborated to define the scope of the problem, identify challenges in the current process, and provide suggestions for improving the process. Results: The group found there is a need for better differentiation between the three main stages of feasibility, and the four sub-phases of Site Feasibility. The discussion brought to light emerging trends like early initiation of Site Feasibility and premature engagement of sites by CROs. To fully explain these challenges, the group analyzed the current practices and documented their downstream impact on clinical trial execution for all stakeholders. A list of best practices emerged naturally from this analysis. These findings are aggregated into short and actionable best practice guides. Conclusion: The task force suggests practical changes for the feasibility process and raises awareness of emerging trends and their associated risks. This awareness can begin to drive change in the site feasibility process, although industry-wide transformation will require new levels of collaboration, data standardization and automation tools. The potential benefits of evolving this process are significant and meaningful for more efficient and successful clinical trials.
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The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor TIE-2/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Receptor TIE-2/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.
Assuntos
Sondas Moleculares , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Cristalografia por Raios X , Modelos Moleculares , Nicotina/síntese química , EstereoisomerismoRESUMO
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.