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先导化合物的发现药物化学最困难的问题是发现先导化合物(Lead compound)。通过周密的药物设计发现先导化合物方面,迄今只有少数几个成功的例子。如Wilson(1955)设计具有亲核性的2-PAM,能逆转被磷酸酯抑制的乙酰胆碱酯酶;Baker(1967)设计一类不可逆酶抑制剂,它含的烃化基团可能并不直接作用于酶的活性区域;Reidenberg(1980)采用部分Free-Wilson药物设计方法,根据红斑狼疮病人属于遗传性慢速忆酰化表型(Slow genetic acetylator),
Discovery of Lead Compounds The most difficult issue in pharmaceutical chemistry is the discovery of lead compounds. Only a few successful examples have so far been found in the discovery of lead compounds through careful drug design. For example, Wilson (1955) designed a nucleophilic 2-PAM to reverse the phosphorylation of acetylcholinesterase. Baker (1967) designed a class of irreversible enzyme inhibitors whose alkylating groups may not act directly Reidenberg (1980) used part of the Free-Wilson drug design method, according to the patients with lupus erythematosus is a genetic inherited slow-type amyloidosis (Slow genetic acetylator)