James T. Link

A method for preparing C-glycosides related to phlorizin

Abstract Johnsons Suzuki coupling protocol was employed to prepare C -glycoside analogs of phlorizin ( 1 ). In vitro biological evaluation of these C -glycosides indicated the anomeric oxygen is important to the SGLT inhibitory activity of phlorizin ( 1 ) and related agents.

Discovery and SAR of diarylsulfide cyclopropylamide LFA-1/ICAM-1 interaction antagonists

Diarylsulfide cyclopropylamides were synthesized and evaluated as LFA-1/ICAM-1 interaction antagonists. A substituent pattern was identified which maximized potency and minimized protein binding as exemplified by antagonist 30 (IC50 = 5 nM).

Progress towards glucagon receptor antagonist therapy for Type 2 diabetes

Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon function. Several research groups have discovered small molecule glucagon antagonists from multiple chemical series and at least one has been clinically evaluated. Although multiple compounds have blocked the rise in blood glucose levels in response to a glucagon challenge, no preclinical or clinical efficacy data from chronic studies have been reported. In general, drug candidate potency, pharmacokinetics, physical properties and cross-species potency have hindered progress and preclinical efficacy assessment. Recently, antisense oligonucleotides against the glucagon receptor have been described, providing a guiding post for the type of activity a small molecule glucagon antagonist may possess, as well as offering a potential therapeutic strategy.

An evaluation of a C-glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist.

A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.