Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres.

Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

Globalization, food and health in Pacific Island countries.

Pacific Island countries (PICs) are experiencing an epidemic of obesity and consequent chronic diseases. Despite investment in the development of National Plans of Action for Nutrition (NPANs) and interventions to promote healthy eating and physical activity, nutritional status appears to show little improvement. This paper presents a synthesis of the findings from two research papers that were prepared for a 2003 food safety and quality meeting in Nadi, Fiji. The findings indicate that although lifestyle behaviours might be the immediate cause of dietary imbalances, greater attention should focus on omnipresent influences of globalization as a critical element of the nutrition transition in the Pacific. In particular, those aspects of globalization mediated through the World Trade Organization (WTO) Agreements that are placing pressures on food security and fostering increased dependence on imported food of poor nutritional quality. Rapid, significant and sustainable improvements in public health in PICs require interventions that can tackle these underlying contributors to ill health. There are opportunities to explore the use of food regulatory approaches to influence the composition, availability and accessibility of food products. Within the context of the WTO Agreements the legitimacy of food regulatory approaches will depend upon the case to demonstrate the relationship between the intervention and the protection of food security and public health nutrition. The challenges in realising these opportunities are: 1) to have the capacity to construct a case, 2) meet the technical and financial demands to administer and enforce regulatory approaches, and 3) to take advantage of opportunities available and to be able to fully participate in the international policy-making process.