Patent Evaluation: Arylethanolamine derivatives and their use as β₃-adrenoceptor agonists

Summary

Novelty: Novel arylethanolamine derivatives are claimed to be β₃-adrenoreceptor agonists. They are stated to show good selectivity for β₃-rather than β1- or β2-adrenoreceptors. They are potentially useful for the treatment of hyperglycaemia and obesity.

Biology: Lipolysis stimulated by β-agonists was demonstrated in rat white adipocytes, according to the method of Rodbell (J. Biol. Chem. (1964) 239:375–380) and the modification of Honnor et al. (J. Biol. Chem. (1985) 260:15122–15129). The specified compound had an EC₅₀ of 41.7nM (intrinsic activity = 1.0). In vitro, β1- and β2- adrenoceptor agonist activity was studied using rat atrial preparations and rat uterine preparations, respectively. The specified compound demonstrated K_i values of 7610nM and 3656nM for β1- and β2- adrenoceptors, respectively.

Chemistry: Five compounds are disclosed and are exemplified by synthesis. Yields, mps, optical rotations and nmr data are given. Two compounds are specifically claimed including the (R)-4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxyacetic acid, sodium salt.