Chemokine receptor antagonists from discovery to the clinic

被引:0
作者
Horuk, R [1 ]
机构
[1] Berlex Labs Inc, Richmond, CA 94804 USA
来源
LEUCOCYTE TRAFFICKING: THE ROLE OF FUCOSYLTRANSFERASES AND SELECTINS | 2004年 / 44卷
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暂无
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Chemokine receptors belong to one of the most pharmacologically exploited proteins; the G-protein coupled receptors (GPCRs). Drugs that target these receptors make up greater than 45% of all known marketed medicines. The first recorded uses of drugs directed at this important family of proteins can be traced back to ancient Chinese and Indian physicians who were using plant extracts to treat a variety of disorders (Ding 1987; Sevenet 1991). For example, although tetrahydropalmitine, a potent dopamine receptor antagonist, was isolated only a few years ago from the fumewort plant, the plant itself was first described for its tranquilizing effects as early as the fifth century (Ding 1987). Extracts from the deadly nightshade family have been widely used as analgesics and anesthetics in medicine since ancient times (Ding 1987). The active principles, identified as the alkaloids atropine and scopolamine, are potent musacarinic receptor antagonists. From the ancient shaman who searched for medicinal plants to treat disease (often with much trial and error until the right combinations were found) to the modern pharmaceutical industry with its sophisticated high-throughput mechanism-based screening programs; the quest to find drugs to help the sick and ailing is an ongoing process that has been around since the dawn of mankind. Today the modem pharmaceutical houses concentrate ever-increasing resources and money on finding potent drugs that target both old diseases such as multiple sclerosis and rheumatoid arthritis, and modem diseases such as AIDS and organ transplant rejection. Collectively, the chemokines, because of their important role in these and other diseases, have been the focus of much attention by drug companies, and almost all of the major pharmaceutical houses have screens to identify chemokine receptor antagonists. Several excellent reviews published recently have concentrated on the biology, pathophysiology and molecular mechanisms of action of the chemokines (Gerard and Rollins 2001; Mackay 2001; Thelen 2001) and the reader is directed toward them to gain a thorough understanding of the importance of this growing family of proteins. Although some background will be given here to aid in an understanding of the medical importance of chemokines, this review will focus on the rapid advances that have been made in identifying and characterizing chemokine receptor antagonists by discussing their efficacy in animal models of disease as well as in detailing their progression through human clinical trials.
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页码:169 / 190
页数:22
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