Novel corticotropin-releasing factor (CRF) receptor antagonists as effective anxiolytics

Mental disorders are common throughout the world. In the US, which represents the largest market for CNS therapeutics, an estimated 22% of adults suffer from a diagnosable mental disorder in a given year, translating to about 44.3 million people. Anxiety disorders are the most common of mental illnesses and include panic disorder, phobias, extreme shyness, obsessive-compulsive behaviors and generalized anxiety, which together disrupt the lives of an estimated 15% of the population. Depressive disorders are also common, albeit less common than anxiety affecting 9.5% of the US population, and include major depression, bipolar disorder and dysthymic disorder. Importantly, there is significant comorbity amongst the various mental disorders and for example, 50-60% of individuals with major depression report a lifetime history of one or more anxiety disorders.

Development in the antidepressant market has been largely limited to targeting the monamines and despite the development of newer antidepressants, undesirable side effects remain a problem, as does the slow onset of activity. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoaminergic synapse. The results of recent novel developmental approaches have suggested that modulation of N-methyl-D-aspartate (NMDA) or NK1 receptors may provide an entirely new set of potential therapeutic targets although recent clinical studies have called into doubt the proof of concept supporting the utility of NK1 receptor antagonists. A further target attracting considerable interest is corticotropin-releasing factor (CRF) receptors.

CRF is a hypothalamic hormone that coordinates neuroendocrine, autonomic and behavioral responses to stress by stimulating the release of ACTH. Hypersecretion of CRF in the CNS has been observed in patients with depression and various anxiety disorders. Levels correlate with disease severity and drop back down to basal levels following treatment. CRF activates two receptor subtypes, CRF1 and CRF2 and antagonism of the former has been identified as a strategy for the treatment of anxiety and depression.

Bristol-Myers Squibb researchers have recently developed a series of 2-arylamino-4-trifluoromethyl-aminomethylthiazole antagonists of the CRF1 receptor. In their recent Bioorganic & Medicinal Chemistry Letters publication, Dubowchik et al report SAR studies around this series which was optimized producing antagonists with binding affinities at the human CRF1 receptor as low as 8nM, a value comparable with the reference compounds, CP-154,526 and NBI-27914. The lead compound described by Dubowchik et al demonstrated good brain penetration and an acceptable half-life, although oral bioavailability was limited. Evaluation in a mouse model of anxiety revealed therapeutic activity at doses of around 30mg/kg of a similar magnitude to that of an equivalent dose of CP-154,526 suggesting that further development of this series may produce effective anxiolytics.

Entry date Tuesday, December 16, 2003

Adapted from Dubowchik et al, Bioorg Med Chem Lett. 2003 Nov 17;13(22):3997-4000.