RESUMO
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Assuntos
Antineoplásicos/química , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Descoberta de Drogas , Cloridrato de Fingolimode , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-AtividadeRESUMO
CONTEXT: Collaborative action is required to address persistent and systematic health inequities which exist for most diseases in most countries of the world. OBJECTIVES: The Academic NGO initiative (ACANGO) described in this paper was set up as a focused network giving priority to twinned partnerships between Academic research centres and community-based NGOs. ACANGO aims to capture the strengths of both in order to build consensus among stakeholders, engage the community, focus on leadership training, shared management and resource development and deployment. METHODS: A conceptual model was developed through a series of community consultations. This model was tested with four academic-community challenge projects based in Kenya, Canada, Thailand and Rwanda and an online forum and coordinating hub based at the University of Ottawa. FINDINGS: Between February 2005 and February 2007, each of the four challenge projects was able to show specific outputs, outcomes and impacts related to enhancing health equity through the relevant production and application of knowledge. CONCLUSIONS: The ACANGO initiative model and network has demonstrated success in enhancing the production and use of knowledge in program design and implementation for vulnerable populations.
