期刊
EXPERT OPINION ON INVESTIGATIONAL DRUGS
卷 13, 期 7, 页码 799-828出版社
TAYLOR & FRANCIS LTD
DOI: 10.1517/13543784.13.7.799
关键词
anxiety; anxiolytic; corticotropin-releasing factor receptor antagonist; corticotropin-releasing; hormone receptor antagonist; depression; nonpeptide; small molecule; stress
资金
- NIDDK NIH HHS [DK64871, DK26741] Funding Source: Medline
Preclinical studies suggest that the brain corticotropin-releasing factor (CRF) systems mediate anxiety-like behavioural and somatic responses through actions at the CRF1 receptor. CRF1 antagonists block the anxiogenic-like effects of CRF and stress in animal models. Cerebrospinal fluid levels of CRF are elevated in some anxiety disorders and normalise with effective treatment, further implicating CRF systems as a therapeutic target. Prototypical CRF1 antagonists are highly lipophilic, non-competitive antagonist-, of peptide ligands. Modification of the chemotype and the identification of novel pharmacophores are yielding more drug-like structures with increased hydrophilicity at physiological pHs. Newer compounds exhibit improved solubility, pharmacokinetic properties, potency and efficacy. Several clinical candidates have entered Phase I/II trials. However, unmet challenges await resolution during further discovery, clinical development and therapeutic application of CRF1 antagonists.
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