Discovery and Structure−Activity Relationship of N-(Ureidoalkyl)-Benzyl-Piperidines As Potent Small Molecule CC Chemokine Receptor-3 (CCR3) Antagonists
Journal of Medicinal Chemistry2002Vol. 45(17), pp. 3794–3804
Citations Over TimeTop 13% of 2002 papers
George V. De Lucca, Ui T. Kim, Curt Johnson, Brian J. Vargo, Patricia K. Welch, Maryanne Covington, Paul Davies, Kimberly A. Solomon, Robert Newton, George L. Trainor, Carl P. Decicco, Soo S. Ko
Abstract
Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.
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