Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3, 2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.

During investigations of the basic reactivity of siliranes, Seyferth observed that hexamethylsilirane (1) undergoes insertion of aldehydes to afford oxasilacyclopentane 2 (eq l).1•2 345678Since this silirane was the only one examined, the stereochemistry and regiochemistry of this carbon-carbon bond-forming process have not been investigated, although this information would provide vital clues about the reaction mechanism. In fact, little is known about the scope of silirane chemistry.2-8 We have discovered that siliranes undergo stereochemically and regiochemically defined insertions of aldehydes, and the outcome is determined by the reaction conditions. Furthermore, siliranes were used for the synthesis of diols such as 4 in two steps (aldehyde insertion and oxidation) from the silirane trans-3, which can be obtained by silacyclopropanation of (£>2-butene (eq 2).9

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1-((1R,2R)-2-Hydroxy-1-methyl-2-phenylethyl)-1-methyl-3-(4-phenoxyphenyl)urea (1) was identified as a hit from the screening of the neuropeptide Y5 (NPY5) receptor. This lead was optimized for in vitro potency by changing the stereochemistry, the phenylethyl segment, the urea portion, and the 4-phenoxyphenyl group on the molecule. Over 40 analogues of 1 were prepared to study the structure-activity relationship for this series. The most potent compounds in this class have IC(50)s less than 0.1 nM at the NPY5 receptor (e.g., 40f, 44a, and 47). To determine the functional activity for this series of compounds, selected analogues were tested in a cellular assay measuring forskolin-induced cyclic AMP accumulation in 293 cells transfected with the human NPY5 receptor. All urea analogues tested in the functional assay acted as antagonists (e.g., 1, 32, 40a, and 44e).

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