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Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome |
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| 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 |
| Institution: | a Discovery R&D AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, United States b Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham B15 2SQ, UK c Creative Pharmacology Solutions LLC, 10532 Coppergate, Carmel, IN 46032, United States |
| Abstract: | 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. |
| Keywords: | 5-HT3 receptor partial agonist Irritable bowel syndrome IBS Ligand-gated ion channel Ramosetron Alosetron Indole Indazole |
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