Max Planck Institute of Psychiatry, Kraepelinsr, Munich, Germany.
Expert Opin Investig Drugs. 2011 Apr;20(4):519-35. doi: 10.1517/13543784.2011.565330.
Major depressive disorder is a serious and common psychiatric illness, and many of the depressive patients benefit from pharmacological treatment. Available antidepressants produce remission in only about 30 -- 40% of the patients. Therefore, new concepts are being explored for the development of innovative antidepressants with higher efficacy.
The use of corticotropin releasing factor type 1 (CRF1) receptor antagonists for depression is supported by abundant evidence of target validation, the availability of in vitro and in vivo assays and specific small ligands. Some of these compounds have advanced to clinical studies, with discouraging results so far in depression. This review covers the development of CRF1 receptor antagonists at different stages of the development pipeline of the pharmaceutical industry and its bottlenecks. Most of the available CRF1 receptor antagonists known so far share a common chemical scaffold. We present possible strategies to overcome obstacles in the discovery and development process at the levels of library screenings and clinical studies to find more diverse compounds.
CRF1 receptor antagonists are expected to be beneficial only for those patients with CRF overexpression and the need for tests to identify these individuals is discussed. New technical developments and diagnostic tools might eventually lead to a more successful treatment of major depression with CRF1 receptor antagonists.
重度抑郁症是一种严重且常见的精神疾病，许多抑郁症患者受益于药物治疗。现有的抗抑郁药仅能使约 30-40%的患者得到缓解。因此，人们正在探索新的概念，以开发疗效更高的创新型抗抑郁药。
大量的靶点验证证据、体外和体内检测以及特定的小分子配体支持使用促肾上腺皮质激素释放因子 1（CRF1）受体拮抗剂治疗抑郁症。其中一些化合物已进入临床研究，但迄今为止在抑郁症方面的结果令人沮丧。这篇综述涵盖了制药行业药物开发管道不同阶段的 CRF1 受体拮抗剂的开发情况及其瓶颈。迄今为止已知的大多数可用的 CRF1 受体拮抗剂具有共同的化学结构。我们提出了在药物筛选和临床研究水平上克服发现和开发过程中障碍的可能策略，以寻找更多样化的化合物。
CRF1 受体拮抗剂预计仅对那些 CRF 过表达的患者有益，因此需要讨论进行这些检测来识别这些患者的必要性。新的技术发展和诊断工具最终可能会使 CRF1 受体拮抗剂更成功地治疗重度抑郁症。
