Corticotropin-releasing factor (CRF) is a well-known regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is activated in response to stress. Hyperactivity of the HPA axis has been linked to depression in humans, and both the elevation of CRF concentrations in the cerebral spinal fluid (CSF) and an increase in the number of CRF-containing neurons in the paraventricular nucleus have been observed in depressed patients. In addition, some antidepressants (e.g., desipramine and fluoxe-tine) have been shown to decrease CRF levels in the CSF. Furthermore, a number of CRF1 antagonists exhibits anxiolytic and antidepressant activity in certain animal models [37,38]. For example, antalarmin (CP-154,526) produces antidepressant-like responses in the rat learned helplessness and mouse chronic mild stress models of depression. Several CRF1 antagonists have reached human clinical trials, but to date
only one has published data: R121919/NBI-30775, 19, demonstrated antidepressant efficacy in a small open-label Phase II study. Unfortunately, this compound was terminated due to increased liver enzymes .
Further SAR efforts on 19 included reduction of the conformational freedom by incorporation into a tricyclic core in an attempt to alter PK properties. A resulting compound, NBI-35965, 20, (pK = 8.5) reduced CRF-induced ACTH release in normal rats (MED = 10mg/kg, p.o.) and was active in the restraint stress model of ACTH release in mice at 20mg/kg, po . Further modification to a more polar core generated 21 (K; = 2nM), which significantly attenuated CRF-induced ACTH release at 10mg/kg, p.o. . Activity in depression models was not reported.
Like the majority of CRF-1 antagonists, R278995/CRA0450, 22, failed to show any effect in rodent behavioral despair models such as rat forced swim and mouse tail suspension tests. However, 22 was active after acute administration in the learned helplessness paradigm. It was also active acutely and chronically (10-day dosing) in the rat olfactory bulbectomy model of depression .
SSR125543, 23, was orally active in the rat forced swim test (30mg/kg, p.o.), and showed positive effects in the mouse chronic mild stress paradigm . Another particulary interesting feature of 23 was the demonstration of neurogenesis in mice after chronic (28-day) dosing . This observation is noteworthy since increased neurogenesis has been shown to result from chronic treatment with clinically effective antidepressants and may be important for an efficacious response .
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