Synthesis and biological evaluation of novel hexahydro-pyrido [ 3 0 , 2 0 : 4 , 5 ] pyrrolo [ 1 , 2-a ] pyrazines as potent and selective 5-HT 2 C receptor agonists

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3 0,2 0:4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3 0, 2 0:4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT2C receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties. 2005 Elsevier Ltd. All rights reserved. Obesity is steadily increasing all over the world 1 and is a major risk factor in the development of hyperglycemia, hypertension, dyslipidemia, coronary artery disease, and certain cancers. The currently approved drugs for the long-term treatment of obesity are the appetite suppressant Sibutramine , a centrally acting mixed noradrenaline/ serotonin-reuptake inhibitor, and Xenical , a non-systemic acting lipase inhibitor which increases the fecal loss of undigested triglycerides. Recent evidence of the utility of 5-HT2C receptor agonists as appetite suppressants in the management of obesity has led to a resurgence of interest in selective and safe 5-HT2C receptor agonists. In preclinical studies, the involvement of the 5-HT2C receptor subtype in the control of feeding in animals 0960-894X/$ see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.11.083