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We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.

Antagonism of cannabinoid-1 (CB 1 ) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB 1 -mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB 1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure−activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB 1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB 1 receptor antagonists.

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Potent and Selective, Sulfamide-Based Human β 3 -Adrenergic Receptor Agonists. -[design, synthesis and evaluation of biological activity of a novel series of highly potent and selective β3-AR agonists such as (VII) and (XIII)]. -(DOW*, R. L.; PAIGHT, E. S.; SCHNEIDER, S. R.; HADCOCK, J. R.; HARGROVE, D. M.; MARTIN, K. A.; MAURER, T. S.; NARDONE, N. A.; TESS, D. A.; DASILVA-JARDINE, P.; Bioorg. Med. Chem. Lett. 14 (2004) 12, 3235-3240; Cardiovasc. Metab. Dis., Pfizer Global Res. Dev., Groton, CT 06340, USA; Eng.) -M. Schroeter 40-139

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