A multivalent approach to the design and discovery of orally efficacious 5-HT4 receptor agonists
| Autor: | Scott R. Armstrong, Seok-Ki Choi, Jeng-Pyng Shaw, David Beattie, Goldblum Adam A, S. Derek Turner, Daniel D. Long, R. Murray McKinnell, Ross G. Vickery, Daniel Marquess, Paul R. Fatheree, Jacqueline A.M. Smith, Roland Gendron, Patrick P. Humphrey |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Male Tegaserod medicine.drug_class Gastrointestinal Diseases Movement 5-HT4 receptor Administration Oral Biological Availability Pharmacology Piperazines Cell Line Substrate Specificity Rats Sprague-Dawley Serotonin 5-HT4 Receptor Agonists Dogs Oral administration Drug Discovery medicine Animals Humans Binding site Receptor chemistry.chemical_classification Binding Sites Chemistry Sulfonamide Rats Biochemistry Drug Design Molecular Medicine Receptors Serotonin 5-HT4 medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 52(17) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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