Piperidine amides as 11beta-hydroxysteroid dehydrogenase type 1 inhibitors

A series of piperidine amide inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were identified via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented.     

Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1

2,5,5-Trisubstituted oxazolones were identified as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The synthesis, structure-activity relationship and metabolic stability of these compounds are presented.     

Bis-aryl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1

3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.     

Adamantyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1

Adamantyl triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.     

Phenylcyclobutyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I

3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.     

4-Methyl-5-phenyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I

4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.     

Distinctive molecular inhibition mechanisms for selective inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.     

Novel non-steroidal inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates glucocorticoid action at the pre-receptor stage by converting cortisone to cortisol. 11β-HSD1 is selectively expressed in many tissues including the liver and adipose tissue where metabolic events are important. Metabolic syndrome relates to a number of metabolic abnormalities and currently has a prevalence of >20% in adult Americans. 11β-HSD1 inhibitors are being investigated by many major pharmaceutical companies for type 2 diabetes and other abnormalities associated with metabolic syndrome. In this area of intense interest a number of structural types of 11β-HSD1 inhibitor have been identified. It is important to have an array of structural types as the physicochemical properties of the compounds will determine tissue distribution, HPA effects, and ultimately clinical utility. Here we report the discovery and synthesis of three structurally different series of novel 11β-HSD1 inhibitors that inhibit human 11β-HSD1 in the low micromolar range. Docking studies with 1–3 into the crystal structure of human 11β-HSD1 reveal how the molecules may interact with the enzyme and cofactor and give further scope for structure based drug design in the optimisation of these series.     

Novel 18beta-glycyrrhetinic acid analogues as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenases

Extensive structural modifications to the 18beta-glycyrrhetinic acid template are described and their effects on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. Isoform selective inhibitors have been discovered and compound 7 N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide is highlighted as a very potent selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50) = 4pM.     

7alpha- and 7beta-hydroxy-epiandrosterone as substrates and inhibitors for the human 11beta-hydroxysteroid dehydrogenase type 1

The human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes both the NADP(H)-dependent oxido-reduction of cortisol and cortisone and the inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) through a 7-oxo-DHEA intermediate. As shown with human liver and intestine fractions, 7alpha-hydroxy-epiandrosterone (7alpha-hydroxy-EpiA) and 7beta-hydroxy-EpiA were readily inter-converted with no evidence for a 7-oxo-EpiA intermediate. Whether this inter-conversion resulted from action of the 11beta-HSD1 or from an unknown epimerase is unresolved. Furthermore, whether these steroids could inhibit the cortisol-cortisone oxido-reduction remains a question. The recombinant human 11beta-HSD1 was used to test these questions. NADP(+) supplementation only provided the production of 7beta-hydroxy-EpiA out of 7alpha-hydroxy-EpiA with a V(max)/K(M) ratio at 0.1. With NADPH supplementation, both 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA were formed in low amounts from 7beta-hydroxy-EpiA and 7alpha-hydroxy-EpiA, respectively. These inter-conversions occurred without a trace of the putative 7-oxo-EpiA intermediate. In contrast, the 7-oxo-EpiA substrate was efficiently reduced into 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, with V(max)/K(M) ratios of 23.6 and 5.8, respectively. Competitive and mixed type inhibitions of the 11beta-HSD1-mediated cortisol oxidation were exerted by 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, respectively. The 11beta-HSD1-mediated cortisone reduction was inhibited in a competitive manner by 7-oxo-EpiA. These findings suggest that the active site of the human 11beta-HSD1 may carry out directly the epimeric transformation of 7-hydroxylated EpiA substrates. The low amounts of these steroids in human do not support a physiological importance for modulation of the glucocorticoid status in tissues.     

A novel 18 beta-glycyrrhetinic acid analogue as a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase 2

Using 18beta-glycyrrhetinic acid as a template, the synthesis of a series of secondary amides at the 30-position is described and the effects of these modifications on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. An isoform selective inhibitor has been discovered and compound 5, N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide, is highlighted as a very potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50)=4 pM.     

Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1)

High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).     

beta-Keto sulfones as inhibitors of 11beta-hydroxysteroid dehydrogenase type I and the mechanism of action

The design, synthesis, and biological evaluation of beta-keto sulfones as 11beta-HSD1 inhibitors and the mechanism of inhibition are described here. This class of compounds is not active against 11beta-HSD2 and therefore may have therapeutic potential for metabolic syndrome and type 2 diabetes.     

Discovery of novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 by docking and pharmacophore modeling

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a potential target for treatment of diabetes and metabolic syndrome. Docking and pharmacophore modeling have been used to discover novel inhibitors of 11beta-HSD1. Several compounds, with large structural diversity and good potency against 11beta-HSD1, have been found and their potency was determined by the enzyme assay. New scaffolds of 11beta-HSD1 inhibitors are also reported.     

Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I

The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeutic potential for metabolic syndrome, type 2 diabetes and related metabolic dysfunctions.     

Novel enzymological profiles of human 11beta-hydroxysteroid dehydrogenase type 1

The human enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the reversible oxidoreduction of 11beta-OH/11-oxo groups of glucocorticoid hormones. Besides this important endocrinological property, the type 1 isozyme (11beta-HSD1) mediates reductive phase I reactions of several carbonyl group bearing xenobiotics, including drugs, insecticides and carcinogens. The aim of this study was to explore novel substrate specificities of human 11beta-HSD1, using heterologously expressed protein in the yeast system Pichia pastoris. In addition to established phase I xenobiotic substrates, it is now demonstrated that transformed yeast strains catalyze the reduction of ketoprofen to its hydroxy metabolite, and the oxidation of the prodrug DFU-lactol to the pharmacologically active lactone compound. Purified recombinant 11beta-HSD1 mediated oxidative reactions, however, the labile reductive activity component could not be maintained. In conclusion, evidence is provided that human 11beta-HSD1 in vitro is involved in phase I reactions of anti-inflammatory non-steroidal drugs like ketoprofen and DFU-lactol.     

Synthesis and structure–activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R¹ and R² respectively, was explored with a focus on improving the inhibitory activity (IC₅₀) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile.     

Glucocorticoids, 11 beta-hydroxysteroid dehydrogenase type 1, and visceral obesity

Glucocorticoids are implicated as a pathophysiological mediator of obesity and its accompanying metabolic and cardiovascular complications. Obese patients exhibit normal circulating cortisol levels, related to increased glucocorticoid production and degradation. However, it has been demonstrated that local production of active cortisol from inactive cortisone driven by 11 beta-hydroxysteroid dehydrogenase type 1 is exaggerated in adipose tissue of obese subjects. Such local hypercortisolism may be responsible for increased adipocyte differentiation and enhanced secretion of free fatty acids and other substances involved in the metabolic and cardiovascular complications observed in obesity.     

Cloning of chicken 11beta-hydroxysteroid dehydrogenase type 1 and its tissue distribution

11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) is an enzyme that interconverts active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inactive 11-oxo derivatives (cortisone, 11-dehydrocorticosterone). Although bidirectional, it is considered to operate in vivo as an 11-reductase that regenerates active glucocorticoids and thus amplifies their local activity in mammals. Here we report the cloning, characterization and tissue distribution of chicken 11HSD1 (ch11HSD1). Its cDNA predicts a protein of 300 amino acids that share 51-56% sequence identity with known mammalian 11HSD1 proteins, while in contrast to most mammals, ch11HSD1 contains only one N-linked glycosylation site. Analysis of the tissue distribution pattern by RT-PCR revealed that ch11HSD1 is expressed in a large variety of tissues, with high expression in the liver, kidney and intestine, and weak in the gonads, brain and heart. 11-Reductase activity has been found in the liver, kidney, intestine and gonads with low or almost zero activity in the brain and heart. These results provide evidence for a role of 11HSD1 as a tissue-specific regulator of glucocorticoid action in non-mammalian vertebrates and may serve as a suitable model for further analysis of 11HSD1 evolution in vertebrates.