世界卫生组织（WHO）已确认肥胖是一种疾病，并向全世界宣布："肥胖症将成为全球首要健康问题"。因此，开发有效的减肥药物是急待解决的问题。减肥药的市场需求量大，开发减肥药物具有广阔的前景。下面是发表在science 上的文章，我翻译出来，希望对肥胖药物开发提供一些思路
开发有效的减肥药物是制药行业的梦想，然困难重重，原因很简单，肥胖是一种复杂的疾病。减肥药物会损害机体的生化代谢，这是生死攸关的问题。饮食中枢信号传递使用与其他生理过程相同的神经递质及受体。靶向神经递质及其受体的的药物，可能导致严重的副作用。目前，减肥药物包括以下几类：
食欲抑制：三分天下
1，Xenical ，脂肪酶阻断剂，但脂肪不是唯一代谢紊乱的营养成分，而且其可导致抽筋和严重的腹泻，减肥效果不明显，和单纯节食相比，只减重2-3%， 且停药后很快反弹
2，Meridia（欧洲市场称为Reductil） ，学名sibutramine，属于amphetamine类化合物，可阻断突触对神经递质noradrenaline和serotonin的重吸收，但这两种物质同时调控其他代谢过程，因此起副作用明显，可导致血压升高，1998-2001，150人服用Meridia者住院，29人死亡，19人由于心血管疾病。FDA正在调查，意大利已经停止其销售
3，Phentermine 和fenfluramine 联用，商品名为fen-phen，其fenfluramine成分已经与1997年因导致心脏瓣膜疾病而被FDA禁止销售。
未来的减肥药：
4，大麻受体抑制剂：Rimonabant。 大麻类受体可导致食欲亢进，其资料有限，因其开发商口风很紧。
5，CNTF：大约10年以前，发现了CNTF，其 作为治疗肌萎缩性侧索硬化药物，但后来发现其可导致恶病质，与此同时，相继发现瘦素（leptin）及其受体，传递脂肪储存量高，减低食欲和代谢。CNTF受体和leptin 受体结构和功能类似，通过对大脑摄食中枢的弓状核而发挥作用,但他们有一点关键的差别：对体重过重者，leptin不具有减肥疗效，肥胖者体内含有足够多的leptin，也就是说，他们是leptin 抗性的。
而在动物实验和人，CNTF对肥胖者有显著的减肥效果
Regeneron 开发了基因修饰的CNTF，Ⅱ期临床显示其具有减肥效果，一些国家的Ⅲ 期临床也结束，结果令人兴奋。
CNTF可能是通过促使大脑产生抑制性的神经肽如 -melanocyte-stimulating hormone ( -MSH),并且阻断产生其他神经元产生食欲刺激分子，如neuropeptide Y (NPY) and agouti-related peptide (AGRP)，
CNTF可帮助机体获得新的调控点，保持苗条体形。
6，Leptin 的脂肪细胞受体：
melanocortin receptors (MCR-3 and MCR-4)，日益成为热点，可能绕过令人讨厌的leptin 抗性问题。这一领域的竞争异常激烈
Neurocrine Biosciences Inc. 关于MCR-4靶向的药物有可能在明年进行临床实验
Merck 和 Chiron大公司有类似的临床前资料
7，饮食的阴阳调节分子：ghrelin在饭前达到高潮，而PYY3-36 在饱腹后达到高潮， ghrelin 于1999年发现，在胃肠产生，作用于垂体的生长激素细胞，以及诱导弓状核细胞释放NPY 和AGRP。
PYY3-36 是NPY家族成员，2002年发现，其和NPY竞争下丘脑相同的受体。 PYY3-36 可抑制食欲，但单独的PYY3-36 给肥胖者，不能降低体重
减肥药的开发，尤其是有效的减肥药，是一艰巨的工作，可以说至今为止
市场上，还没有特别成功的减肥药，但肥胖却越来越成为社会问题，所以我认为，肥胖药品市场很有潜力，但是对疗效好副作用小的减肥药。减肥药物可以开发，但要慎重
likejun:能告知你的文章的出处吗？最好也把原文贴出来
http://www.sciencemag.org/cgi/reprint/299/5608/849
Obesity Drug Pipeline Not So Fat
Trisha Gura*
Eating right and exercising be damned; the search is on for drugs that can control obesity
Drugmakers have been salivating over the prospect of creating antiobesity medications. Obesity is a rising pandemic that includes 60 million adults in the United States alone, and although most physicians champion diet and exercise as the best way to fight fat, many people are desperate for an easier way to avoid corpulence and consequences such as heart disease, stroke, and diabetes. It's a drugmaker's dream.
Prospects looked good in 1994 when the discovery of the fat-regulating hormone leptin blew open the doors to the molecular world of obesity. The discovery promised researchers a colorful vista of new strategies to work with. They are badly needed; only three fat-busting drugs have clawed their way into the marketplace and held on--amid lawsuits, severe side effects, and even, possibly, deaths.
Why aren't there more antiobesity drugs? Quite simply, "it's hard to treat complex diseases," says George Yancopoulos, chief scientific officer and president of Regeneron Laboratories in Tarrytown, New York. Such drugs must tamper with the biochemistry of metabolism; it's an essential system for survival and thus sometimes fatal to disrupt. In addition, appetite circuits in the brain use neurotransmitters and receptors that control other body processes. "If you target these things, you can get terrible side effects," says endocrinologist Stephen Bloom of the Imperial College Faculty of Medicine in London. And that has been the story as obesity pill after hyped obesity pill has come to market.
And yet research, postleptin, is yielding important insights into the body's cast of caloric characters (see p. 846). Some discoveries are nearing the end of the drug-development pipeline, enduring the decade-long time scale of pharmaceutical research and testing. Others are in early clinical trials. More are likely to follow; for example, two hot new molecules appear to influence short-term eating patterns. "Even if today obese individuals or health-care providers are frustrated," says Michael Schwartz of the University of Washington, Seattle, "targets that exist now have the potential to lead to real breakthroughs in the future." 4 1 2 3 4 下一页 尾页
开发有效的减肥药物是制药行业的梦想，然困难重重，原因很简单，肥胖是一种复杂的疾病。减肥药物会损害机体的生化代谢，这是生死攸关的问题。饮食中枢信号传递使用与其他生理过程相同的神经递质及受体。靶向神经递质及其受体的的药物，可能导致严重的副作用。目前，减肥药物包括以下几类：
食欲抑制：三分天下
1，Xenical ，脂肪酶阻断剂，但脂肪不是唯一代谢紊乱的营养成分，而且其可导致抽筋和严重的腹泻，减肥效果不明显，和单纯节食相比，只减重2-3%， 且停药后很快反弹
2，Meridia（欧洲市场称为Reductil） ，学名sibutramine，属于amphetamine类化合物，可阻断突触对神经递质noradrenaline和serotonin的重吸收，但这两种物质同时调控其他代谢过程，因此起副作用明显，可导致血压升高，1998-2001，150人服用Meridia者住院，29人死亡，19人由于心血管疾病。FDA正在调查，意大利已经停止其销售
3，Phentermine 和fenfluramine 联用，商品名为fen-phen，其fenfluramine成分已经与1997年因导致心脏瓣膜疾病而被FDA禁止销售。
未来的减肥药：
4，大麻受体抑制剂：Rimonabant。 大麻类受体可导致食欲亢进，其资料有限，因其开发商口风很紧。
5，CNTF：大约10年以前，发现了CNTF，其 作为治疗肌萎缩性侧索硬化药物，但后来发现其可导致恶病质，与此同时，相继发现瘦素（leptin）及其受体，传递脂肪储存量高，减低食欲和代谢。CNTF受体和leptin 受体结构和功能类似，通过对大脑摄食中枢的弓状核而发挥作用,但他们有一点关键的差别：对体重过重者，leptin不具有减肥疗效，肥胖者体内含有足够多的leptin，也就是说，他们是leptin 抗性的。
而在动物实验和人，CNTF对肥胖者有显著的减肥效果
Regeneron 开发了基因修饰的CNTF，Ⅱ期临床显示其具有减肥效果，一些国家的Ⅲ 期临床也结束，结果令人兴奋。
CNTF可能是通过促使大脑产生抑制性的神经肽如 -melanocyte-stimulating hormone ( -MSH),并且阻断产生其他神经元产生食欲刺激分子，如neuropeptide Y (NPY) and agouti-related peptide (AGRP)，
CNTF可帮助机体获得新的调控点，保持苗条体形。
6，Leptin 的脂肪细胞受体：
melanocortin receptors (MCR-3 and MCR-4)，日益成为热点，可能绕过令人讨厌的leptin 抗性问题。这一领域的竞争异常激烈
Neurocrine Biosciences Inc. 关于MCR-4靶向的药物有可能在明年进行临床实验
Merck 和 Chiron大公司有类似的临床前资料
7，饮食的阴阳调节分子：ghrelin在饭前达到高潮，而PYY3-36 在饱腹后达到高潮， ghrelin 于1999年发现，在胃肠产生，作用于垂体的生长激素细胞，以及诱导弓状核细胞释放NPY 和AGRP。
PYY3-36 是NPY家族成员，2002年发现，其和NPY竞争下丘脑相同的受体。 PYY3-36 可抑制食欲，但单独的PYY3-36 给肥胖者，不能降低体重
减肥药的开发，尤其是有效的减肥药，是一艰巨的工作，可以说至今为止
市场上，还没有特别成功的减肥药，但肥胖却越来越成为社会问题，所以我认为，肥胖药品市场很有潜力，但是对疗效好副作用小的减肥药。减肥药物可以开发，但要慎重
likejun:能告知你的文章的出处吗？最好也把原文贴出来
http://www.sciencemag.org/cgi/reprint/299/5608/849
Obesity Drug Pipeline Not So Fat
Trisha Gura*
Eating right and exercising be damned; the search is on for drugs that can control obesity
Drugmakers have been salivating over the prospect of creating antiobesity medications. Obesity is a rising pandemic that includes 60 million adults in the United States alone, and although most physicians champion diet and exercise as the best way to fight fat, many people are desperate for an easier way to avoid corpulence and consequences such as heart disease, stroke, and diabetes. It's a drugmaker's dream.
Prospects looked good in 1994 when the discovery of the fat-regulating hormone leptin blew open the doors to the molecular world of obesity. The discovery promised researchers a colorful vista of new strategies to work with. They are badly needed; only three fat-busting drugs have clawed their way into the marketplace and held on--amid lawsuits, severe side effects, and even, possibly, deaths.
Why aren't there more antiobesity drugs? Quite simply, "it's hard to treat complex diseases," says George Yancopoulos, chief scientific officer and president of Regeneron Laboratories in Tarrytown, New York. Such drugs must tamper with the biochemistry of metabolism; it's an essential system for survival and thus sometimes fatal to disrupt. In addition, appetite circuits in the brain use neurotransmitters and receptors that control other body processes. "If you target these things, you can get terrible side effects," says endocrinologist Stephen Bloom of the Imperial College Faculty of Medicine in London. And that has been the story as obesity pill after hyped obesity pill has come to market.
And yet research, postleptin, is yielding important insights into the body's cast of caloric characters (see p. 846). Some discoveries are nearing the end of the drug-development pipeline, enduring the decade-long time scale of pharmaceutical research and testing. Others are in early clinical trials. More are likely to follow; for example, two hot new molecules appear to influence short-term eating patterns. "Even if today obese individuals or health-care providers are frustrated," says Michael Schwartz of the University of Washington, Seattle, "targets that exist now have the potential to lead to real breakthroughs in the future." 4 1 2 3 4 下一页 尾页