A multivalent approach to the design and discovery of orally efficacious 5-HT4 receptor agonists.
J Med Chem
; 52(17): 5330-43, 2009 Sep 10.
Article
en En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Agonistas del Receptor de Serotonina 5-HT4
/
Enfermedades Gastrointestinales
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Año:
2009
Tipo del documento:
Article