Free-Wilson and correlation analysis were combined to study a series of 34 pepstatin analogues in which mainly position 2 was varied. A statistically highly significant correlation was found between the inhibitory activity of the analogues on an enriched plasma renin preparation and structural parameters of the amino acid side chain in position 2. The crucial parameters were found to be the NMR chemical shift of the alpha-carbon, the localized electrical (inductive) effect, and the van der Waals radius related steric parameter, which demonstrated the dominating influence of electronic inductive effects compared to steric bulk. The model gives insight into the structural requirements for effective inhibition and suggests the histidine-2 derivative, a positive outlier in this series, as a lead compound for further structure-activity studies.

Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central vasopressin V 1b receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active vasopressin V 1b receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V 1b receptors and displays a highly selective profile with regard to a large number of receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V 1b receptor activation by AVP, such as intracellular Ca 2+ increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 53 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.

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