Recent Advances in Small Molecule Antagonists of the Corticotropin- Releasing Factor Type-1 Receptor-Focus on Pharmacology and Pharmacokinetics

Abstract

Corticotropin-releasing factor (CRF), a 41-amino acid peptide, has been recognized as an important factor mediating stress. Efforts to discover small molecule antagonists of the CRF type-1 receptor (CRF(1)-R) for potentially novel treatment of anxiety and depression started in the early 1990's. Although highly potent in vitro and efficacious in animal models, early reported compounds such as CP-154,526 and NBI-27914 are highly lipophilic and possess high plasma protein and tissue binding, long elimination half life, and toxicity, likely due in part to accumulation in tissues. Recently, several laboratories have reported potent CRF(1)-R antagonists with improved physicochemical properties. Compounds such as DMP696, NBI-30775/R121919 and R278995/CRA0450 possess at least one additional polar group in their structures and are therefore less lipophilic than the earlier compounds, while still maintaining high potency. For example, DMP696 has a K(i) value of 1.7 nM and a cLogP of 3.2, which is similar to CP-154,526 in potency but about 4-log units lower in partition coefficient. Despite its high plasma protein binding (98.5% in rat), DMP696 occupies over 50% of brain CRF(1)-R at a total plasma concentration above 100 nM, which is consistent with the doses that produce anxiolytic effects in the rat defense withdrawal test of anxiety. This article will review small molecule CRF(1)-R antagonists by focusing on their pharmacological and pharmacokinetic properties. In addition, the pharmacology of small molecules binding to the CRF(1) receptor will be discussed. An orally available compound with desirable properties in these categories will have a good chance to be developed into a novel treatment for anxiety and depression which may be devoid of the side effects of existing antidepressant treatments.