Obesity Drug Update The Lost Decade 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 3494-3521; doi:10.3390/ph3123494 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Obesity Drug Update: The Lost Decade? Fayi Yao and Robert George MacKenzie * Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine Detroit, MI 48201, USA * Author to whom correspondence should be addressed; E-Mail: rmackenz@; Tel.: +1-313-577-0677; Fax: +1-313-577-9469. Received: 05 October 2010; in revised form: 17 November 2010/ Accepted: 23 November 2010/ Published: 24 November 2010 Abstract: The growing worldwide obesity epidemic and obesity-related disorders present a huge unmet medical need for safe and effective anti-obesity medications. The discovery of leptin in 1994 was rapidly succeeded by a wave of related discoveries leading to the elaboration of a hypothalamic melanocortinergic neuronal circuit regulated by leptin and other central and peripheral signaling molecules to control energy homeostasis. The identification of specific neuronal subtypes along with their unique connections and expression products generated a rich target menu for anti-obesity drug discovery programs. Over the course of the last decade, several new chemical entities aimed at these targets have reached various stages or successfully completed the drug discovery/regulatory process only to be dropped or taken off the market. There are now in fact fewer options for anti-obesity drug therapies in late 2010 than were available in 2000. The challenge to discover safe and effective anti-obesity drugs is alive and well. Keywords: obesity; anti-obesity drug targets; anti-obesity drugs; hypothalamus 1. Introduction Obesity is a major health problem that results when energy intake exceeds energy output with the excess being stored as fat in adipose tissue and ectopically in other tissues. Developing in an environment of nu