Ralph Howe

ICI D7114 a novel selective β‐adrenoceptor agonist selectively stimulates brown fat and increases whole‐body oxygen consumption

1 ICI D7114 is a novel, β‐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, 0.04 mg kg−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 β‐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 β2‐adrenoceptors. 5 The results indicate that ICI D7114 may have activity at atypical β‐adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.

Selective .beta.3-adrenergic agonists of brown adipose tissue and thermogenesis. 1. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetates

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has 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 10. Potency was generally markedly reduced by placing substituents on the phenyl ring of the phenoxypropanolamine unit of 8; only the 2-fluoro analogue 16 had comparable potency to 8. Other structure-activity relationships are discussed. Further testing of 8 (ICI 198157) has shown that in the rat 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. It increases metabolic rate, as judged by an increase in oxygen consumption, and in the genetically obese Zucker rat it causes a reduced rate of weight gain. This class of compound may be useful in the treatment of obesity in man.

ICI D7114: a novel selective adrenoceptor agonist of brown fat and thermogenesis.

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.

Microbial modification of diosgenin and hecogenin

On incubation with an unidentified bacterium diosgenin [(25R)-spirost-5-en-3β-ol](1) was converted into (25R)-9-oxode-AB-spirostane-8α-propionic acid (3). Incubation with Nocardia globerula produced the same oxo-acid (3) and also a small amount of its 1 7α-hydroxy-derivative. Surprisingly, hecogenin [(25R)-3β-hydroxy-5α-spirostan-12-one](2) was also converted into the oxo-acid (3) by the bacterium; thus in the course of metabolism a 12-oxo-group had been replaced by a methylene group. A metabolic pathway is suggested for that replacement, based on the isolation of the minor metabolite (25R)-12α-hydroxyspirost-4-en-3-one.

Application of the Bucherer hydantoin synthesis to diacetyl mono-oxime. The mechanism of the Bucherer reaction, and the constitution of the hypothetical ‘ dimethylbishydantoin ’ of Bucherer and lieb

The major product obtained when the Bucherer conditions for hydantoin synthesis were applied to diacetyl mono-oxime was (3aRS,6aSR)-6-amino-1,3,3a,6a-tetrahydro-1-hydroxy-3a,6a-dimethylpyrrolo[3,4-d]imidazole-2,4-dione (3). Two minor products (7) and (9) are related to (3) but a third, the imidazole 1-oxide (10), is not. Compound (10) was obtained from diacetyl mono-oxime and ammonium carbonate in the absence of cyanide. It is proposed that 4,4-disubstituted 5-imino-oxazolidin-2-ones (18), postulated by Bucherer and Steiner to be intermediates in hydantoin syntheses, rearrange to hydantoins by a base catalysed E1cB mechanism. It is further proposed that (3) is the hypothetical ‘dimethylbishydantoin ’(35) reported by Bucherer and Lieb in 1934.