A multivalent approach to the design and discovery of orally efficacious 5-HT4 receptor agonists.

Full 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.

Author information

Author/s: McKinnell, R Murray (RM); Armstrong, Scott R (SR); Beattie, David T (DT); Choi, Seok-Ki (SK); Fatheree, Paul R (PR); Gendron, Roland A L (RA); Goldblum, Adam (A); Humphrey, Patrick P (PP); Long, Daniel D (DD); Marquess, Daniel G (DG); Shaw, J P (JP); Smith, Jacqueline A M (JA); Turner, S Derek (SD); Vickery, Ross G (RG);

Affiliation: Department of Medicinal Chemistry, Theravance, Inc., San Francisco, California 94080, USA. mmckinnell(-atsign-)theravance.com

Journal and publication information

Publication Type: Journal Article

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2009-Sep; vol 52 (issue 17) : pp 5330-43

Dates: Created 2009/09/03; Completed 2009/09/25;

PMID: 19663444, status: MEDLINE (last retrieved date: 9/25/2009)

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