【摘 要】
：
Corticotrophin-releasing factor (CRF),a 41 amino acid peptide,is a key regulator of the hypothalamic-pituitary-adrenal axis in response to stress.It has shown to play an important role in coordinating
【机 构】
：
YLCPharma LLC Waterford USA
【出 处】
：
中国上海第七届国际新药发明科技年会
论文部分内容阅读
Corticotrophin-releasing factor (CRF),a 41 amino acid peptide,is a key regulator of the hypothalamic-pituitary-adrenal axis in response to stress.It has shown to play an important role in coordinating neuroendocrine,autonomic and behavior effects to stressors.Over-expression of CRF is thought to be involved in several disease states that are induced by stress,including anxiety,depression,addiction,irritable bowel syndrome,and congestive heart failure.A selective CRF1 receptor antagonist thought to be useful for treatment of diseases induced by stress.We have previously discovered a pyrro-pyrimidine series in which CP-154526 and Antalarmin represent the first centrally and orally active CRF1 antagonists.Both compounds have been widely used as research tools to test the CRF hypothesis in preclinical models that were induced by stressors.Extensive structure-activity relationships (SAR) were explored by modifying the substituents and bicyclic template of pyrro-pyrimidine ring,which led to the discovery of a structurally diverse monocyclic pyridine series,in which CP-316311 was advanced to Phase Ⅱ depression trials to test the hypothesis that CRF 1 antagonists could be used clinically as antidepressant drugs.CP-316311 showed a significant positive food effect in dogs and humans after oral administration.Efforts to address the food effect issue led us to explore and discover CP-376395 as an orally active CRF1 receptor antagonist,which showed improved physicochemical properties while retaining desired pharmacological properties.CP-376395 was selected for further development,due not only to its reduced food effects,but also its greater efficacy in CNS models.CP-376395 was advanced to the clinic.The synthesis of representative candidates and their in vitro,ex vivo,in vivo and PK data are discussed.
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