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

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Manning DD, Cioffi CL, Usyatinsky A, Fitzpatrick K, Masih L, Guo C, Zhang Z, Choo SH, Sikkander MI, Ryan KN, Naginskaya J, Hassler C, Dobritsa S, Wierschke JD, Earley WG, Butler AS, Brady CA, Barnes NM, Cohen ML, Guzzo PR

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

Bioorg Med Chem Lett. 2011 Jan 1;21(1):58-61. doi: 10.1016/j.bmcl.2010.11.080. Epub 2010 Nov 21.

PubMed ID
21146988 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Alosetron5-hydroxytryptamine receptor 3AKi (nM)0.5N/AN/ADetails
AlosetronCytochrome P450 3A4IC 50 (nM)600N/AN/ADetails