The
ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]
acetate (1) (R1 = OMe) had previously been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related
acid 1 (R1 =
OH).
Amides have been examined to determine whether they have advantages over the
ester. In particular, in the rat and dog the half-lives of
amides of appropriate potency were no longer than those of the
ester. The
amide (S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2- methoxyethyl)phenoxyacetamide [
S-27,
ICI D7114] was selected as having properties consistent with a
sustained-release formulation should that prove necessary. Unlike the
ester it is resistant to hydrolysis in the gut lumen. Further testing of
ICI D7114 has shown that in the rat, cat, and dog it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1- and beta 2-adrenergic receptors in other tissues. Slimming effects were observed in the dog.
ICI D7114 may be a selective thermogenic agent in man and may be useful in the treatment of
obesity and diabetes.