Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor.
ABSTRACT Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
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ABSTRACT: 3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor were obtained with the CoMFA standard model (q (2) = 0.787, r (2) = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q (2) = 0.809, r (2) = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl derivatives and predict their activity prior to synthesis.Journal of Molecular Modeling 05/2007; 13(4):519-29. · 1.98 Impact Factor
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ABSTRACT: Chemokines belong to a family of chemotactic cytokines that direct the migration of immune cells towards sites of inflammation. They mediate their biological effects by binding to cell surface receptors, which belong to the G protein-coupled receptor superfamily. Since chemokines and their receptors have been implicated in the pathophysiology of a number of autoinflammatory diseases, chemokine receptor antagonists could prove to be useful therapeutics to target these diseases. Here, we review the role of chemokines in autoimmunity, concentrating mainly on the chemokine receptors CCR1 and CCR5, and discuss the potential utility of antagonists that target these 2 receptors as they progress through the clinic.Pharmacology [?] Therapeutics 08/2005; 107(1):44-58. · 7.79 Impact Factor