A multivalent approach to the design and discovery of orally efficacious 5-HT4 receptor agonists.
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.
McKinnell
R Murray
RM
Department of Medicinal Chemistry, Theravance, Inc., San Francisco, California 94080, USA. mmckinnell@theravance.com
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
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009068:Movement / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D013379:Substrate Specificity
D010879:Piperazines; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4