mk-0916 and Metabolic-Syndrome

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme primarily responsible for the regulation of intracellular cortisol levels. Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. Emerging literature also supports a potential role in the treatment of other unmet medical needs including Alzheimer's disease, vascular inflammation, cardiovascular disease, and glaucoma. The aim of this article is to review the medicinal chemistry literature around small molecule approaches to developing synthetic inhibitors of 11β-HSD1 and to highlight key compounds that have resulted from the efforts of both industrial and academic groups. The reported data from 11β-HSD1 inhibitors that have progressed into the clinic are summarized followed by a perspective from the authors.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Alzheimer Disease; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Glaucoma; Glucocorticoids; Humans; Metabolic Syndrome

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