Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 58 - 61
• Main Authors: Manning, David D., Cioffi, Christopher L., Usyatinsky, Alexander, Fitzpatrick, Kevin, Masih, Liaqat, Guo, Cheng, Zhang, Zhenjun, Choo, Sok Hui, Sikkander, M. Inthikhab, Ryan, Kristen N., Naginskaya, Jennifer, Hassler, Carla, Dobritsa, Svetlana, Wierschke, Jonathan D., Earley, William G., Butler, Amy S., Brady, Catherine A., Barnes, Nicholas M., Cohen, Marlene L., Guzzo, Peter R.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: 5-HT3 receptor partial agonist; agonists; Alosetron; Animals; binding capacity; Biological and medical sciences; Cell Line; Digestive system; Disease Models, Animal; Humans; IBS; Imidazoles - chemistry; Indazole; Indole; Indoles - chemistry; Irritable bowel syndrome; Irritable Bowel Syndrome - drug therapy; Ligand-gated ion channel; Medical sciences; Mice; Microsomes, Liver - metabolism; new drugs; Pharmacology. Drug treatments; Ramosetron; Receptors, Serotonin, 5-HT3 - chemistry; Receptors, Serotonin, 5-HT3 - metabolism; serotonin; Serotonin 5-HT3 Receptor Agonists - chemical synthesis; Serotonin 5-HT3 Receptor Agonists - chemistry; Serotonin 5-HT3 Receptor Agonists - therapeutic use; Alosetron; Indole; Irritable bowel syndrome; Indazole; IBS; Ramosetron; 5-HT3 receptor partial agonist; Ligand-gated ion channel; Partial agonist; Quinuclidine derivatives; Ligand; Rodentia; Lactam; Oral administration; receptor partial agonist; Ionic channel; Vertebrata; Mammalia; Treatment; Mouse; Animal; 5-HT3 Serotonine receptor; Chemical synthesis; 5-HT
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.11.080

Selective, low intrinsic activity 5-HT3 receptor partial agonists with good oral activity are described. Serotonin type 3 (5-HT3) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT3A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT3A receptor were measured for the indazole series. Excellent 5-HT3 receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold–Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.