References

Rivier and J. Rivier, Science, 1981, 213, 1394. 2 M. E. Keck, Amino Acids, 2006, 31, 241. 3 T. L. Bale, Hormones Behav., 2006, 50, 529. 4 J. H. Kehne, CNS Neurol. Disord. Drug Targets, 2007, 6, 163. 5 E. Arzt and F. Holsboer, Trends Pharmacol. Sci., 2006, 27, 531. 6 V. B. Risbrough and M. B. Stein, Hormones Behav., 2006, 50, 550. 7 F. Holsboer and M. Ising, Eur. J. Pharmacol, 2008, 583, 350. 8 C. F. Hemley, A. McCluskey and P. A. Keller, Curr. Drug Targets, 2007, 8,...

Eating disorders

High states of stress or anxiety may exacerbate a variety of eating disorders including binge eating, anorexia nervosa, and bulimia nervosa 51 . Alleviation of stress and anxiety by antagonism of CRF receptors may be useful for the treatment of these maladaptive eating habits. Yohimbine, an a-2 adrenoceptor antagonist commonly used to induce stress- and anxiety-like symptoms in humans and non-humans, causes stress- and anxiety-induced reinstatement of food-seeking in rats 84 . CRF-R1 antagonist...

Preclinical Studies

The majority of the known pharmacology of ROCK has been determined with two inhibitors, neither of which was originally designed to inhibit rho kinase. Fasudil (HA-1077, 1) and Y-27632 (2) have been used extensively to investigate the function of ROCK in cellular and whole animal environments. Compound 1 was approved in Japan in 1995 as a drug for the treatment of cerebral vasospasm, thus becoming the first protein kinase inhibitor drug approved for human treatment 13-14 . Compound 1 inhibits...

Info

Additional progress toward Cat S selective inhibitors has been reported. The pyrazole-based inhibitor JNJ-10329670 (27) has Cat S potency (IC50 100 nM), selectivity over other cathepsins including Cats K and L (IC50 > 50 mM), activity in a cellular assay measuring inhibition of cleavage of the invariant chain in JY cells (IC50 600-800 nM), and an acceptable pharmacokinetic profile 80 . Azaindole 28 demonstrated increased Cat S potency against the enzyme (IC50 30 nM) and in the cellular assay...

Tryptase inhibitors

The major enzymes stored and secreted by mast cells are tryptase and chymase, which play key roles in asthma. Their actions include inflammation, tissue remodeling, bronchial hyperresponsiveness 17 , and -adrenergic desensitiza-tion of airway smooth muscle 18 . Several mechanisms have been proposed for the role of tryptase in allergic inflammation, including promoting histamine release and recruiting leukocytes. In addition, tryptase has an effect on narrowing of the bronchial lumen, promoting...

Clinical Findings With Crfr1 Antagonists

This section will review CRF-R1 antagonists for which clinical trial results have been published, as well as compounds currently reported to be in clinical trials. While a number of companies have actively pursued progression of CRF-R1 antagonists into the clinic, results of these trials have appeared for only a small number of compounds 7 . The first clinical efficacy results were reported in 2000 from an open-label study with R121919 NBI-30775 (36) in patients with major depressive disorder...