mk-0916 has been researched along with Body-Weight* in 2 studies
2 other study(ies) available for mk-0916 and Body-Weight
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Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adamantane; Animals; Blood Glucose; Body Weight; Brain; Crystallography, X-Ray; Cyclopropanes; Diabetes Mellitus, Type 2; Dietary Fats; Humans; Hypoglycemic Agents; Insulin; Isoenzymes; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Molecular; Pyrazoles; Rats; Stereoisomerism; Structure-Activity Relationship; Thiazoles | 2014 |
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms.
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)-fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting "off-target" mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1-independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a "step-change" treatment for diabetes and/or obesity. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain; Dietary Fats; Dose-Response Relationship, Drug; Energy Metabolism; Female; Gene Expression Regulation, Enzymologic; Genotype; Glucose; Hypoglycemic Agents; Insulin; Liver; Male; Mice; Mice, Knockout; Molecular Structure; Pyrazoles; Pyrimidines; RNA, Messenger; Triazoles | 2013 |