Increasing energy expenditure by treatment with thermogenic drugs is not new, but available drugs have suffered from the problem of lack of selectivity. In the last decade two key findings have allowed the development of selective thermogenic drugs that have promise in the treatment of obesity. 1) The recognition that brown adipose tissue (BAT) plays a role in compensatory increases in energy expenditure has allowed an approach directed at a target organ. 2) The demonstration showing that increases in the activity of BAT may be modulated by an atypical (beta 3) adrenoceptor has led to the development of a new peripherally acting beta-adrenoceptor agonist ICI D7114, which stimulates thermogenesis at doses that have little effect on beta 1 or beta 2 adrenoceptors. Treatment with the compound activates BAT and thermogenesis even in species and situations where the intrinsic capacity is low. 3) The compound has beneficial effects in animal models of obesity and disturbed glucose and lipid homeostasis.

1 ICI D7114 is a novel, fi-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04mgkg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg 1, p.o.) with no chronotropic effects on the heart at these doses.2 Reference fl-adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses. 3 Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge. 4 Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at /12-adrenoceptors. 5The results indicate that ICI D7114 may have activity at atypical fi-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.

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The optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine have been prepared and absolute configurations have been assigned. In their action on the central nervous system the S isomers are at least ten times more potent than the R isomers. The intermediate 4-benzyl-2-(p-toluensulfonyloxymethyl)tetrahydro-1,4-oxazine has been resolved. Its isomers provide a convenient starting point for the preparation of optical isomers of viloxazine analogues of known configuration.

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.