Steven H. Olson

11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice

The enzyme 11β–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11β-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11β-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11β-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11β-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.

Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-β-lactamase

BACKGROUNDnHigh level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems.nnnRESULTSnBiphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis.nnnCONCLUSIONSnBPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.

Phenylcyclobutyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.

4-Methyl-5-phenyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.

Coumermycin-induced dimerization of GyrB-containing fusion proteins.

Publisher Summary The coumermycin-GyrB system is a useful strategy for regulating protein homodimerization and activation both in cell extracts and in intact cell culture systems. Coumermycin-based dimerization strategies are currently being used to identify biological responses (such as changes in gene transcription) induced by the Raf and Jak/signal transducers and activators of transcription (STAT) signal transduction pathways. As the utility of dimerization-based strategies becomes evident, they are applied to an increasing number of signal transduction pathways. An important development in this process is the generation of heterodimeric reagents incorporating GyrB-binding groups. The relative ease by which novobiocin can be synthetically modified to incorporate novel chemical entities should permit facile development of such reagents. It is interesting to investigate how specific pathways interact by using chemically distinct dimerization methods to regulate the activity of each independently. Such approaches provide important insights into the overall regulation of cell signaling.

Synthesis of coumermycin A1

Abstract A concise synthesis of the antibiotic coumermycin A 1 , a natural product isolated from streptomyces , was achieved. In a key step, a selectively protected noviose sugar was prepared from novobiocin through a transglycosylation reaction with acetone.