The University of Edinburgh

Brian Robert Walker

Jonathan Robert Seckl

Christopher Richard Watkin Edwards

Hazel Joan Dyke

Thomas David Pallin

Trevor Robert Perrior

Peter Ward

Scott Peter Webster

Ruth Andrew

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, 3,3-disubstituted-(6-aza-bicyclo[3.1.1]hept-6-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, and 4,4-disubstituted piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds of the following formula that, inter alia, inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1 (11&#x3b2;-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc. 

3,3-disubstituted-(8-aza-bicyclo[3.2.1]OCT-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanones as inhibitors of 11 (&#x3b2;)-HSD1

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, 3,3-disubstituted-(6-aza-bicyclo[3.1.1]hept-6-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone, and 4,4-disubstituted piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds of the following formula that, inter alia, inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1 (11&#x3b2;-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.

3,3-disubstituted-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanones as inhibitors of 11 (&#x3b2;)-HSD1

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain (4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds that, inter alia, inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1 (11&#x3b2;-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.

(4-phenyl-piperidin-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds and their use

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain amido-thiophene compounds that, inter alia, inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1 (11&#x3b2;-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11&#x3b2;-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.

Amido-thiophene compounds and their use

Amido-thiophene compounds and their use as 11-beta-HSD1 inhibitors

The present invention relates to the modulation of glucocorticoid metabolism. In particular the invention relates to the modulation of the functional activity of the glucocorticoid receptor by 5&#x3b1; reduced metabolic breakdown products of glucocorticoids.

Treatment of inflammation with 5&#x3b1; reduced metabolites

This invention relates to the interconversion of inactive 11-keto steroids with their active 11B-hydroxy equivalents, to methods by which the conversion of the inactive to the active form may be controlled, and to useful therapeutic effects which may be obtained as a result of such control. More specifically, but not exclusively, the invention is concerned with interconversion between cortisone and cortisol in humans.

Regulation of intracellular glucocorticoid concentrations

This invention relates to the interconversion of inactive 11-keto steroids with their active 11B-hydroxy equivalents, to methods by which the conversion of the inactive to the active from may be controlled, and to useful therapeutic effects which may be obtained as a result of such control. More specifically, but not exclusively, the invention is concerned with interconversion between cortisone and cortisol in humans.

Therefore, another aspect of the invention is a method for determining whether a compound or composition is a regulator of intracellular glucocorticoid activity in adipose tissue comprising determining whether said compound or composition inhibits reductase activity of 11-Beta-hydroxysteroid dehydrogenase 1 (11-Beta HSD1) in said tissue.

The interconversion of inactive 11-keto steroids with their active 11&bgr;-hydroxy equivalents can be controlled by the use of inhibitors of the 11&bgr;-reductase enzyme, such as carbenoxolone (3&bgr;-(3-carboxypropionyloxy)-11-oxo-olean-2-en30-oic acid). Such inhibitors may be put to a number of therapeutic uses in humans and animals, for instance to inhibit hepatic gluconeogenesis, to lower intracellular cortisol concentration, to increase insulin sensitivity in adipose tissue and muscle, and to prevent or reduce neuronal loss/cognitive impaiment due to glucocorticoid potentiated neurotoxicity or neural dysfunction or damage.

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Edinburgh, United Kingdom

Brian Robert Walker