palonosetron and Irritable-Bowel-Syndrome

Serotonin type 3 (5-HT(3)) 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-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) 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.

Topics: Animals; Cell Line; Disease Models, Animal; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Mice; Microsomes, Liver; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Agonists