Stoit Axel Reinhard, Lange Jos Hubertus Maria, Hartog Arnold Peter den, Ronken Eric, Tipker Koos, Stuivenberg Herman Heinrich van, Dijksman Jessica Adriana Rigtje, Wals Henri Cornelis, Kruse Chris Gerrit
Solvay Pharmaceuticals, Research Laboratories, Weesp, The Netherlands.
Chem Pharm Bull (Tokyo). 2002 Aug;50(8):1109-13. doi: 10.1248/cpb.50.1109.
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha, gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.2) as well as very potent antagonistic activity (pA2=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.
本文描述了高效的基于吡唑的三环CB1受体拮抗剂(2)的设计、合成及生物活性。关键的合成步骤涉及锂化的α,γ-酮酯加合物(4)的闭环反应。该系列中的最佳硝基衍生物(28)在体外表现出高CB1受体亲和力(pKi = 7.2)以及非常强的拮抗活性(pA2 = 8.8)。结果表明，吡唑环闭合的区域选择性强烈依赖于所用芳基肼的芳族取代模式。
