title: Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome.
abstract: 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.
authors.affiliation: Discovery R&D AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, United States. David.Manning@amriglobal.com
authors.forename: David D
authors.initials: DD
authors.lastname: Manning
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cioffi
authors.forename: Alexander
authors.initials: A
authors.lastname: Usyatinsky
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzpatrick
authors.forename: Liaqat
authors.initials: L
authors.lastname: Masih
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sok Hui
authors.initials: SH
authors.lastname: Choo
authors.forename: M Inthikhab
authors.initials: MI
authors.lastname: Sikkander
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Ryan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Naginskaya
authors.forename: Carla
authors.initials: C
authors.lastname: Hassler
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dobritsa
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wierschke
authors.forename: William G
authors.initials: WG
authors.lastname: Earley
authors.forename: Amy S
authors.initials: AS
authors.lastname: Butler
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brady
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Peter R
authors.initials: PR
authors.lastname: Guzzo
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D007093:Imidazoles; D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; C029899:imidazole; C030374:indole