n-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin and Diabetes-Mellitus--Type-2

Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as anti-viral agents and as agents against type 2 diabetes. The value of the adamantyl group in drug design is multidimensional. The hydrophobic substituent constant for the adamantyl group has been estimated from the calculated partition coefficients (clogP values) of 31 adamantyl-bearing compounds in the clinic or in development as πadamantyl=3.1, which indicates that the logP value of a compound with high water solubility (logP<<0) could be moved with an adamantyl-based modification to a region that is more clinically useful. The steric bulk of the adamantyl group can: (i) restrict or modulate intramolecular reactivity; and (ii) impede the access of hydrolytic enzymes, thereby increasing drug stability and plasma half life. The value of the adamantyl group in drug design has been recognized most recently in the design of agents to treat iron overload disease (in development), malaria (in clinical trials) and type 2 diabetes (in the clinic).

Topics: Adamantane; Animals; Antimalarials; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Iron Chelating Agents; Iron Overload; Malaria; Solubility

Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.

Topics: Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Gangliosides; Glucose Tolerance Test; Glucosyltransferases; Humans; Liver; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Nude; Phenylalanine; Rats; Rats, Sprague-Dawley; Rats, Zucker; Structure-Activity Relationship; Triglycerides