Medicinal chemistry

Author: Chief Editor: Peng Sixin
Publisher:
Publishing Date: 1999-08-01
Features: This book is divided into 18 chapters, categorized by pharmacological effects or efficacy, introducing the discovery process, structural characteristics, synthetic routes, mechanisms of action, main uses, and structure-activity relationships of various important drugs. The revised edition, while maintaining the basic structure and format of the second edition (edited by Peng Sixin, Chemical Industry Press, 1988), has made significant adjustments to the content, enriching it with new knowledge and discarding outdated sections. For example, two new chapters, "Drug Metabolism" and "Drug Biotechnology," have been added to broaden students' knowledge. Each chapter is accompanied by references or selected readings for further study. In addition to serving as a textbook for pharmaceutical chemistry, pharmacy, and other disciplines in higher medical and pharmaceutical institutions, this book can also be used as a reference for researchers, producers, hospital pharmacies, and other pharmaceutical professionals.
Excerpt: Tetramethylpyrazine,, and emodin. Antimalarial drugs: Artemisinin and its derivatives—dihydroartemisinin, arteether, and artemether—have structures different from known antimalarials, being sesquiterpene lactones containing peroxides, which break the traditional concept of the basic structure of antimalarial drugs and open up new fields for antimalarial research. Artemisinin has shown good efficacy against malignant malaria, especially cerebral malaria resistant to chloroquine, serving as a successful example of discovering new drugs through structural modification of natural active ingredients. Additionally, new antimalarial drugs such as phenylfuroxan and naphthoquine phosphate have been developed, placing China's antimalarial drug research at the world's forefront.
Antiparasitic drugs: Furapromide, emodin, and imidazolyl esters. Contraceptive drugs: Crystalline is used for induced abortion, while gossypol, the first male antifertility drug discovered in China, was not clinically applied due to its tendency to cause hypokalemia. China has conducted systematic research on its chemistry, mechanism of action, and toxicology. The synthetic intermediate of schisandrin,, can reduce SGPT and protect the liver. Two new alkaloids—scopolamine and hyoscine—have been isolated from Hyoscyamus tanguticus: the former is used for toxic shock and improving microcirculatory disorders, while the latter is a cholinergic antagonist.
Analgesics: Tetrahydropalmatine and dihydroetorphine. Rifampicin is a semi-synthetic antibiotic for tuberculosis. Sodium dimercapto succinate is China's first broad-spectrum metal chelating agent to enter the international market.
Basic research, such as the artificial full synthesis of insulin, the chemical and structural studies (primary, secondary, and spatial) of, and new μ-opioid receptor agonists like hydroxymethadone and new potassium channel blockers like benzyltetrahydropalmatine, have also been advanced. Drug design is a central aspect of drug research and an important trend in pharmaceutical chemistry. Since the 1970s, China has begun research in this field, evolving from Hansch methods to 3D-QSAR based on the three-dimensional structures of drugs and biomolecules, significantly enhancing the level of new drug research.
In summary, it can be seen that since the founding of New China, pharmaceutical chemistry has achieved great success. With the development of the pharmaceutical industry, the formulation of the "Nineth Five-Year Plan" and the long-term development plan for 2010, and the implementation of the "Science and Education Revitalize Medicine" strategy, pharmaceutical chemistry will undoubtedly continue to advance, creating better new drugs to serve the health of the people and the sustainable development of the pharmaceutical industry.
### Four. Drug Research and Development (Drug Research and Development)
Internationally, there are currently 3,500 to 4,000 chemical raw materials. Among them, about 50% are synthetic drugs, 30% are active ingredients from animals and plants, 12% are biochemical or microbial drugs, and 8% are inorganic drugs. It is generally believed that most diseases have not yet been satisfactorily treated. For common or highly harmful diseases such as tumors, cardiovascular diseases (including brain diseases), central nervous system disorders, viral and severe infections, AIDS, elderly diseases, and contraceptive drugs, it is necessary to develop new drugs that are highly effective, low-toxic, and of high quality.
Drug research is an interdisciplinary exploration and a creative endeavor that requires coordination among multiple disciplines. In addition to pharmacy, it also involves collaboration from biological sciences, chemical sciences, and clinical medicine. The relationships between disciplines and various stages of drug research can be illustrated in a diagram (Figure 1-1).
Discovering effective compounds is the foundation of research, as previously mentioned, and can come from multiple sources. First, their properties and structures must be determined, followed by biological system tests to understand the compound's pharmacological effects, toxicology, metabolism, and interactions with the body. Then, structure-activity relationship studies are conducted. This information feedback can provide references for the design of new compounds and further insights into the mechanism of action, guiding the design of biological system experiments.
In general, research work is a cyclic process involving drug design, biological system testing, and structure-activity relationships, encompassing interdisciplinary collaboration.
Drug development is based on laboratory research and involves studies for production preparation, such as production processes, pilot-scale expansion, "three-waste" treatment, technical and economic indicators, and market information, to convert research results into products as quickly as possible. Therefore, drug development is the industrialization of the results of basic and applied research in drug-related fields, transforming them into practical productive forces and creating social and economic benefits.
Drug research and development consist of two stages, although there is significant overlap in technical aspects, each stage has distinct focuses. The research stage emphasizes academic and technical significance, while the development stage places greater emphasis on market value and economic significance.
In summary, development is a critical link between drug research and production. A scientific development process, in addition to technical issues, also involves social sciences such as economics, commodity science, statistics, and market analysis.
The research and development of a new drug involve substantial investment and a long cycle, generally divided into the following four stages:
(1) Formulating Research Plans and Preparing Compounds
Based on social needs and the level of scientific development, and after understanding domestic and international research trends, a rigorous new drug research plan and experimental design are formulated. Then, chemical synthesis or natural product extraction is conducted, and the structures and relevant properties of the obtained compounds are determined. This stage involves investigation, data collection, literature review, planning, experimentation, and the preparation of compounds to provide the material foundation for the next stage.
(2) Screening and Preclinical Research
Screening is first conducted using experimental animals. Among the numerous synthesized or extracted compounds, only a few may exhibit the desired activity. Targeted screening for multiple pharmacological indicators remains necessary, as some drugs are discovered through random screening. During screening, experimental animal models should be selected as closely as possible to simulate pathological and therapeutic processes, minimizing the gap between animals and clinical trials. Currently, our screening methods, animal species, quality, and animal housing conditions are still behind those of foreign countries, which has drawn attention from relevant authorities. A national screening center is being actively established.
Effective compounds identified through screening undergo comprehensive preclinical research, including systematic pharmacology, pharmacokinetics, biochemistry, and toxicology. This stage is crucial for determining whether the drug can transition to clinical trials and ensuring its safety and efficacy. Pharmacological experiments must guarantee the drug's effectiveness, while toxicological studies for safety evaluation must be given high priority, including chronic toxicity tests and "three-A" tests (teratogenicity, mutagenicity, and carcinogenicity). Subsequently, in vivo biochemical metabolism and pharmacokinetic studies are conducted, appropriate dosage forms are designed, and quality standards are established.
Since there are differences between experimental animals and humans, before clinical trials, small doses of the drug are first tested on a limited number of healthy volunteers to observe tolerance. If no unexpected side effects occur, the dosage is gradually increased to the expected therapeutic range. Meanwhile, quality standards and dosage form research are further refined. Only after approval by the New Drug Review Committee and authorization from health authorities can the drug enter clinical trials.