Gepirone

Gepirone (BMY 13805, MJ 13805, ORG 13011, Ariza®, Variza) is a pyridinyl piperazine partial 5-HT1A agonist that has anxiolytic effects. It was originally developed by Bristol-Myers Squibb who out-licensed the compound to Fabre-Kramer in 1993.

The U.S.Food and Drugs Administration (FDA) twice rejected approval for Gepirone. First in 2004 and secondly in November 2007.

Gepirone ER was submitted for the preregistration (NDA) phase again in May 2007, after adding additional information from clinical trials as the FDA required in 2004. However, in 2007 it once again failed to convince the FDA of it's qualities for treating depression or anxiety. Fabre-Kramer and GlaxoSmithKline are evaluating the response from the FDA to determine appropriate next steps. Reference: http://www.gsk.com/ControllerServlet?appId=4&pageId=402&newsid=1139

Gepirone is an analogue of buspirone, a substituted imide synthesized by Bristol-Myers in 1968. The slight difference in chemistry between the two molecules (the five membered ring of buspirone is replaced with two methyl groups in gepirone) results in a major difference in pharmacology, namely that the dopaminergic properties of buspirone (high affinity for dopamine D2-like receptors and elevation of dopamine metabolites in vivo) are not shared by gepirone. This discovery led to the realization that the anxiolytic properties of the azapirones were not due to the dopaminergic effects studied at some length with buspirone, but rather to the 5-HT1A receptor effects common to all these molecules. SAR around the gepirone molecule resulted in its choice over several closely-related analogues for further development. For example, substitution with an ethyl group at one of the two methyl groups of gepirone rendered the molecule inactive in the Vogel conflict behavioral test. (Interestingly, replacing both groups with ethyl moieties reduced the potency in this test tenfold but did not eliminate it.)