Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core
Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core
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DOI：
10.1021/jm050070m
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发表时间：
2005-06-16
影响因子：
7.3
通讯作者：
Chen, TK
中科院分区：
文献类型：
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作者：
Dyck, B;Grigoriadis, DE;Chen, TK
通过限制已知的1H-吡咯并[2，3-B]吡啶和1H-吡唑并[3，4-B]吡啶配体，设计了两类新的基于三环的促肾上腺皮质激素释放因子（CRF 1）受体-1拮抗剂。分别发现基于吡咯和吡唑的分子19 g和22 a有效地结合重组CRF 1受体（Ki = 3.5，2.9 nM）并抑制促肾上腺皮质激素（ACTH）从大鼠垂体细胞培养物中释放（IC 50 = 14，6.8 nM）。这些化合物显示出良好的口服生物利用度（F = 24%，7.0%）和大鼠血清半衰期（t（12）= 6.3，12 h），并穿透大鼠大脑（[脑]/[血浆] = 0.27，0.52），但倾向于大体积分布（V-D = 38，44 L kg（-1））和快速清除（CL = 70，43 mL min（-1）kg（-1））。当口服给药时，吡唑和吡咯先导物均剂量依赖性地抑制体内应激诱导的ACTH释放。在30 mg/kg剂量下观察到ACTH减少84-86%。
Two new classes of tricyclic-based corticotropin-releasing factor (CRF1) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF1 receptor (K-i = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC50 = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V-D = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.