Design and synthesis of (ant)-agonists that alter appetite and adiposity.
Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and mechanism-based; and (v) the refinement of selected compound classes, aimed at their clinical use.
Van der Ploeg
Lex H T
LH
Merck Research Laboratories, Boston, MA, USA. lex_van_der_ploeg@merck.com
Kanatani
Akio
A
MacNeil
Douglas
D
Ming Fong
Tung
T
Strack
Alison
A
Nargund
Ravi
R
Guan
Xiao-Ming
XM
D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001066:Appetite / Q000187:drug effects*; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D009478:Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000037:antagonists & inhibitors
D019440:Anti-Obesity Agents; C470072:MC4R protein, human; D009478:Neuropeptide Y; D044105:Receptor, Melanocortin, Type 4