How? Cha langes In Unctional groups Ring structures Configuration(构型) (SAR)
How? Changes in • functional groups • Ring structures • Configuration （构型） （ＳＡＲ）
BETA-BLOCKERS CH3 H3 H 刀cH-cH2-NH-ct cH-cH2-NH一cH O- CH2-CH- CH2--NH--Cl CH3 Dichloroisoproterenol Pronethalol Propranolol 1957 1962 1964 Progress leading to the first commercial beta-blocker. Dichloroisoproterenol-first compound with beta-adrenoceptor blocking action; had partial agonist(sympathomimetic) activity. Pronethalol-beta-adrenoceptor blocking agent, relatively free from sympathomimetic activity Clinical use limited by side effects, including light-headedness, incoordination, nausea and and lacking side effects of pronethalol in humans t agent, free of sympathomimetic activity vomiting. Propranolol-beta-adrenoceptor blocking H ANTAGONISTS (CH2)4NHCNHCH ll CH3 CH2 S(CH2)2NH CNHCH3 H3c CH2S(CH2)2NH CNHCH3 NC= N Burimamide Metiamide Cimetidine" 1972 1973 1975 Progress leading to the first commercial ulcer drug. Burimamide---first histamine H2-receptor blocking agent, poor oral availability. Metiamidehistamine H2-receptor blocking agent, good oral bioavailability. Produced reversible agranulocytosis in some people. Cimetidine histamine H2-receptor blocking agent, good oral bioavailability. No agranulocytosis in man. Final Compound
Mechanism-based drug design involves molecular modification in designing a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process (基于机制的药物设计包括通过分子修饰设 计药物,这种药物能够特异性地影响疾病 过程的已知或可能的生化途径或机制。)
• Mechanism-based drug design involves molecular modification in designing a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process. （基于机制的药物设计包括通过分子修饰设 计药物，这种药物能够特异性地影响疾病 过程的已知或可能的生化途径或机制。）
The intention is the interaction of the drug with specific cell receptors, enzyme systems, the meta bolic processes of pathogens or tumor cels resulting in a blocking, disruption, or reversal of the disease process (设计的意图是影响药物与特异性受体、酶系统、 病原体或癌细胞的代谢途径的相互作用,导致 疾病过程的阻滞、破坏或逆转。)
The intention is the interaction of the drug with • specific cell receptors, • enzyme systems, • the metabolic processes of pathogens or tumor cells, resulting in a blocking, disruption, or reversal of the disease process. （设计的意图是影响药物与特异性受体、酶系统、 病原体或癌细胞的代谢途径的相互作用，导致 疾病过程的阻滞、破坏或逆转。）
Molecular graphics, the use of computer graphics to represent and manipulate the a structure of the drug molecule to“fit”the simulated molecular structure of the receptor site (利用计算机绘图来描绘和操纵药物分子的 结构使之“适合”于受体部位的分子设计 是药物分子设计的有用的和互补的工具
Molecular graphics, the use of computer graphics to represent and manipulate the structure of the drug molecule to “fit” the simulated molecular structure of the receptor site. （利用计算机绘图来描绘和操纵药物分子的 结构使之“适合”于受体部位的分子设计 是药物分子设计的有用的和互补的工具。）