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  • Title: A multivalent approach to the design and discovery of orally efficacious 5-HT4 receptor agonists.
    Author: McKinnell RM, Armstrong SR, Beattie DT, Choi SK, Fatheree PR, Gendron RA, Goldblum A, Humphrey PP, Long DD, Marquess DG, Shaw JP, Smith JA, Turner SD, Vickery RG.
    Journal: J Med Chem; 2009 Sep 10; 52(17):5330-43. PubMed ID: 19663444.
    Abstract:
    5-HT(4) receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT(4) receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a "secondary" binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT(4) agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT(4) agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT(4) agonist for the potential treatment of gastrointestinal motility-related disorders.
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