发现 NBI-77860/GSK561679，一种强效的促肾上腺皮质激素释放因子（CRF1）受体拮抗剂，具有改善的药代动力学性质。
Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties.
机构信息
Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, CA 92130, USA.
出版信息
Bioorg Med Chem Lett. 2010 Dec 15;20(24):7259-64. doi: 10.1016/j.bmcl.2010.10.095. Epub 2010 Oct 25.
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
促肾上腺皮质释放因子（CRF）神经肽的拮抗剂可能在治疗与应激和焦虑相关的疾病方面具有疗效。为了寻找具有更好理化性质的拮抗剂，设计了一系列新的 CRF（1）拮抗剂，旨在用杂环取代吡唑并[1,5-a]嘧啶核心的 C7 位上的丙基。化合物（S）-8d 被鉴定为具有高亲和力的配体，在体外 CRF ACTH 产生测定中，其 pK(i)值为 8.2，pIC(50)值为 7.0，为功能性 CRF(1)拮抗剂。
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