Arvanitis A G, Gilligan P J, Chorvat R J, Cheeseman R S, Christos T E, Bakthavatchalam R, Beck J P, Cocuzza A J, Hobbs F W, Wilde R G, Arnold C, Chidester D, Curry M, He L, Hollis A, Klaczkiewicz J, Krenitsky P J, Rescinito J P, Scholfield E, Culp S, De Souza E B, Fitzgerald L, Grigoriadis D, Tam S W, Shen H L
Department of Chemical and Physical Sciences, DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 1999 Mar 11;42(5):805-18. doi: 10.1021/jm980222w.
Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.
利用大鼠促肾上腺皮质激素释放激素（CRH）受体检测法对我们的化学文库进行筛选，结果发现，与已知的肽拮抗剂α-螺旋CRH(9-41)相比，2-苯胺基嘧啶15-1从大鼠额叶皮质匀浆中置换[125I]-0-酪氨酸-oCRH的能力较弱（Ki = 5700 nM对1 nM）。此外，15-1对同一组织中CRH刺激的腺苷酸环化酶活性的抑制作用较弱，但其效力低于α-螺旋CRH(9-41)（IC50 = 20000 nM对250 nM）。使用克隆的人CRH1受体检测法进行的系统构效关系研究确定了与hCRH1受体最佳结合的药效团。发现了几种高亲和力的2-苯胺基嘧啶和三嗪，其中一些在大鼠体内具有更好的药代动力学特征。本文描述了构效关系研究，这些研究提高了大鼠体内hCRH1受体的结合亲和力和药代动力学参数。相对于早期的先导结构，化合物28-17（平均hCRH1 Ki = 32 nM）在大鼠体内（30 mg/kg时口服生物利用度为19%）以及犬体内（5 mg/kg时口服生物利用度为20%）具有显著改善的药代动力学特征。
