Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders.

摘要: Anxiety and depression are psychiatric disorders that constitute a major health concern worldwide, new pharmacological approaches with the potential for improved efficacy decreased side effect profiles relative to currently marketed drugs desired. Since identification of corticotropin releasing factor (CRF) by Vale colleagues in 1981, an extensive research effort has solidified importance this 41 amino acid peptide mediating body's behavioral, endocrine, autonomic responses stress. The further CRF receptor subtypes provided compelling targets novel pharmaceutical agents. present review focuses on non-peptidic antagonists CRF(1) subtype as therapeutic approach treatment anxiety depression. first section reviews preclinical clinical evidence implicating CRF, general, receptors, particular, Clinical studies have demonstrated dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and/or elevated levels some disorders. Preclinical data utlilizing correlational methods, genetic models, exogenous administration techniques rodents non-human primates supports link between hyperactive pathways anxiogenic depressive-like symptoms. Studies employing use knockouts selective, anxiolytic antidepressant effects under certain types laboratory conditions. A Phase II, open-label, trial depressive disorder reported antagonist was safe effective reducing symptoms In second section, topological is used describe design strategies employed produce potent, antagonists. Two main topologies, featuring center core, top side-chain, pending aromatic ring, can be characterize vast majority known By exploiting these structural elements, pharmacological, physicochemical, pharmacokinetic properties modulated optimized. However, result relatively conservative iteration process during optimization, chemical space presently defined existing still remains fairly narrow. Expanding boundaries, while optimizing "drug-like" antagonists, seems common objective across companies maximize chances success near future.