杂化化合物合成及医药中间体的开发.ppt

2012/05/08;目录:;第一部分;杂环化合物的应用;药物中的杂环化合物;药物设计;发现药物新靶标是产生“重磅炸弹”式创新药物的源头;第二部分;1.1 The Estrogen Receptor (ER，雌激素受体);1.1 雌激素受体分布及功能;; Brzozowski et al. Nature, 1997  Binding Pockets of Estradiol-ERa and Raloxifene-ERa ;传统药效团模式—模拟雌二醇;目标化合物的分子设计与合成;1.2 具有氧（或亚砜）桥双环[2.2.1]庚烯三维结构雌激 素受体配体 Synthesis and Evaluation of Estrogen Receptor Ligands with Bridged bicyclic Cores; 具有立体三维结构的新型ER 配体 New Three-dimensional ER Ligands;氧桥双环[2.2.1]庚烯三维结构配体;呋喃的合成 （Synthesis of Furans）;Diels-Alder Reaction of Furans with Dienophiles;相对结合亲和度 Relative Binding Affinities (E2 = 100%);Transfection assays of 12a and 12b------both are antagonists;Why antagonist? (12a vs 雷洛昔芬 Raloxifene);新型氧杂双桥化合物Novel Estrogen receptor ligands with bridged oxabicyclic cores;呋喃的新法合成 （Synthesis of Furans）;Zhou, H.-B. et al. ChemMedChem. 2012.;Zhou, H.-B. et al. ChemMedChem. 2012.;新型亚砜桥双环化合物 Estrogen Receptor Ligands with Bridged Sulfoxidebicyclic Cores;Zhou, H.-B. et al. J. Med. Chem. 2012.;Table 3. RBA values of subsituted thiophene compounds;;1.3 结构指导稠环吡唑[1,5-a]嘧啶类化合物结构及性能优化;Figure 1. 化合物3与ERa的作用模式（单晶衍射）;Scheme 2. 吡唑[1,5-a]嘧啶类化合物的合成 Synthesis of Pyrazolo[1,5-a]pyrimidine Derivatives Containing A Basic Side Chain ;; 与ER相对结合亲和度;Figure 3. Model of compound 12a ERα(atom colors) compared to raloxifene ERα (green); Methyl-piperidino-pyrazole (MPP), an estrogen receptor a (ERa)-selective antagonist Structurally, MPP is based on and prepared from a pyrazole triol, methyl-pyrazole- triol (MPT), which is an ERα agonist, though of modest potency. Thus, in principle, metabolic cleavage of the BSC might reveal latent agonist activity in an MPT metabolite. ; Notably, other SERMs having aminoethoxy BSCs could, in principle, also be metabolized to more agonistic phenols. To investigate this possibility, we synthesized two MPP analogs in which the side chain was modified so as to preclude an ether metabolic cleavage that could convert MPP to MPT. ;合成 Synthesis;Scheme 1. Structures a