Invited review Prospective therapeutic agents for obesity: Molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists Mayank Kumar Sharma, Prashant R. Murumkar, Ashish M. Kanhed, Rajani Giridhar, Mange Ram Yadav * Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara 390 001, India article info Article history: Received 10 January 2014 Received in revised form 3 April 2014 Accepted 4 April 2014 Available online 5 April 2014 Keywords: Endocannabinoid Cannabinoid 1 (CB1) receptor antagonists Obesity Rimonabant abstract Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacoki- netic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antago- nists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review. Ó 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction 1.1. Obesity According to World Health Organization (WHO), overweight and obesity are defined as abnormal or excessive fat accumulation in body that may impair health. More than1.4 billion adults in the age of 20 and older were overweight in 2008, among which more than 200 million were men and nearly 300 million women were found to be obese. A very jiggered fact is that more than 40 million children under the age of five were obese in 2011. At present, obesity has become the fifth leading risk factor for global deaths [1]. Obesity creates a major risk factor for a number of diseases like cardiovascular diseases, type 2 diabetes, osteoarthritis, hyperten- sion, stroke, sleep apnea, and certain types of cancers [2,3] indicating that obesity is one of the major challenging health problems these days [4]. 1.2. Therapeutic targets for the treatment of obesity Worldwide, researchers are searching for newer targets for the treatment of obesity. Till date various targets have been identified and unfortunately none have provided a potential therapy for obesity. Hence, there is a worldwide demand to develop a “magic bullet” to lose body weight [5]. For the treatment of obesity, peptide targets like cholecystokinin (CCK-1) agonists, glucagon-like peptide 1 (GLP-1) analogs, amylin analogs, neuropeptide Y agonists, peptide YY agonists, ghrelin antagonists, MCH1 receptor antagonists, MC4 receptor agonists and monoamine targets such as 5-HT 2B receptor agonists, 5-HT 6 receptor antagonists, 5-HT 2C agonists, b3 AR ago- nists, dopamine agonists as well as lipase inhibitors, anticonvul- sants, cannabinoid 1 (CB1) receptor antagonists, m-opioid receptor antagonists, sympathomimetic agents, AgRP (agouti-related * Corresponding author. E-mail address: mryadav11@yahoo.co.in (M.R. Yadav). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.04.011 0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 79 (2014) 298e339