Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (K; < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.Corticotropin releasing factor (CRF) is a 41-amino acid peptide initially identified as a hypothalamic factor responsible for stimulating corticotropin (ACTH) secretion from the anterior pituitary (1, 2). CRF causes a rapid increase in plasma ACTH and glucocorticoid levels when given intravenously (3). Activation of the hypothalamic-pituitary-adrenal (HPA) axis can also result from release of CRF from the paraventricular nucleus of the hypothalamus in response to various stressors (1, 4). In the central nervous system, both CRF-like immunoreactivity and high affinity CRF receptors are heterogeneously distributed in the brain (5, 6). Characterizations of these extrahypothalamic CRF systems demonstrate that, in parallel with its actions on the HPA axis, CRF also acts as a neurotransmitter or neuromodulator to coordinate stress-induced neural responses in the brain (7,8).Intracerebroventricular administration of CRF to rats leads to a constellation of neurochemical, neurophysiological, and behavioral sequelae that include activation of central noradrenergic systems and enhancement of behavioral responses to external stimuli (9-13). In this regard, increases in norepinephrine turnover (10) and in the firing rate of locus coeruleus neurons (13) have been observed following CRF injection. Physiological stressors such as nitroprusside infusions also increase locus coeruleus neuronal firing, an effect blocked by a CRF antagonist (a-helical CRF9-41) and consequently thought to be mediated by endogenous CRF (14,15). The response to hemodynamic stress in this case can be desensitized by chronic treatment with tricyclic antidepressants, suggesting that one possible mode of action of antidepressants might be to alter central CRF neurotransmission (16). In behavioral paradigms, CRF injection i.c.v. produces anxiogenic-like effects in several rodent models (e.g. 17-20). These effects are antagonized by central infusion of peptide antagonists (a-helical CRF9-41 and D-Phe CRF12-41), suggesting the involvement of CRF in anxiety and the utility of CRF antagonists as anxiolytics. The persistence ofbehavioral activation in hypophysectomize...

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An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.

A series of 2-aryloxy-4-alkoxy-pyridines ( 1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF 1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF 1 receptor antagonist with an IC 50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine- N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [ (3)H]- 2 as well as the structure-activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF 1 antagonists could be used clinically as antidepressant drugs.