Latest approaches for the treatment of obesity

被引:85
作者
Jackson, V. Margaret [1 ]
Breen, Danna M. [1 ]
Fortin, Jean-Philippe [1 ]
Liou, Alice [1 ]
Kuzmiski, J. Brent [1 ]
Loomis, A. Katrina [2 ]
Rives, Marie-Laure [1 ]
Shah, Bhavik [1 ]
Carpino, Philip A. [3 ]
机构
[1] Pfizer PharmaTherapeut, Cardiovasc & Metab Dis Res Unit, Cambridge, MA 02139 USA
[2] Pfizer PharmaTherapeut, Clin Res, Groton, CT 06340 USA
[3] Pfizer PharmaTherapeut, Cardiovasc & Metab Dis Med Chem, Cambridge, MA 02139 USA
关键词
central nervous system; devices; FGF21; FGFR1c/beta-Klotho; GLP-1; GLP-1R; LepRb; leptin system; MC4R; melanocortin system; microbiome; obesity; GLUCAGON-LIKE PEPTIDE-1; ENDOPLASMIC-RETICULUM STRESS; BLOOD-BRAIN-BARRIER; EARLY-ONSET OBESITY; BODY-MASS INDEX; MELANOCORTIN-4; RECEPTOR; WEIGHT-LOSS; LEPTIN RECEPTOR; ENERGY-EXPENDITURE; CELL-SURFACE;
D O I
10.1517/17460441.2015.1044966
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Introduction: Obesity is a body weight disorder characterized by excess adiposity that increases the risk for developing co-morbidities such as type 2 diabetes. A large medical need exists for new anti-obesity treatments capable of promoting 10% or greater weight loss, with minimal side effects. Areas covered: The authors describe the application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery. Furthermore, they review in detail several pathways and pharmacological targets in the central nervous system (e.g., the leptin-melanocortin axis, the opioid system, GLP-1/GLP-1 system, and FGF21/FGFR1c/beta-Klotho axis) that play an important role in the regulation of feeding behavior and energy homeostasis. Special focus is given to new strategies that engage well-known targets via novel mechanisms in order to circumvent issues seen with previous drug candidates that failed in the clinic. Finally, the authors discuss the recent developments around fixed-dose combinations, targeted polypharmacology, and non-traditional combinations of drugs and devices. Expert opinion: The future for new weight-loss approaches to treat obesity looks promising. Current therapies have shown modest effects on weight loss in the general obese population but will have greater impact in smaller homogeneous sub-populations of obese subjects using personalized medicine. Drug combinations that target multiple, complementary pathways have the potential to promote double-digit weight loss in a broader, heterogeneous patient population. Furthermore, the development of advanced subcutaneous delivery technologies has opened up opportunities to develop breakthrough peptide and biologic agents for the treatment of obesity.
引用
收藏
页码:825 / 839
页数:15
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