Discovery of cyclicsulfonamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors

A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11β-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11β-HSD2.     

Synthesis and evaluation of piperidine urea derivatives as efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitors in diabetic ob/ob mice

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has attracted considerable attention as a potential target for the treatment of diabetes and metabolic syndrome. Herein we report the design, synthesis and efficacy evaluation of novel amide and urea 11β-HSD1 inhibitors. Structure-activity relationship studies led to the identification of 10c, which was efficacious in a diabetic ob/ob mouse model and reduced fasting and non-fasting blood glucose levels after ip dosing.     

Synthesis of 3-spiromorpholinone androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3

Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors. The target compounds exhibited strong inhibition of 17β-HSD3 in rat testis homogenate (87–92% inhibition at 1 μM).     

Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11β-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11β-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1.     

Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors

In the last decade the inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) emerged as a promising new strategy to treat diabetes and several metabolic syndrome phenotypes. Using a molecular modeling approach and classical bioisosteric studies, we discovered a new class of 11β-HSD1 inhibitors bearing an arylsulfonylpiperazine scaffold. Optimization of the initial lead resulted in compound 11 that selectively inhibits 11β-HSD1 (IC₅₀ = 0.7 μM).     

Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11βHSD1.     

Mono-carbonyl curcumin analogues as 11β-hydroxysteroid dehydrogenase 1 inhibitors

A series of structurally novel mono-carbonyl curcumin analogues have been synthesized and biologically evaluated to test their inhibitory potencies and the structure–activity relationship (SAR) on human and rat 11β-hydroxysteroid dehydrogenase isoform (11β-HSD1) activities. 11β-HSD1 selective inhibitors have been discovered and compound A10 is discovered as a very potent with an IC₅₀ value of 97 nM without inhibiting 11β-HSD2.     

Development of 3-substituted-androsterone derivatives as potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3

17Beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Δ?-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3β-substituted-androsterone derivatives and we tested their inhibitory activity on 17β-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17β-HSD3 overexpressed in HEK-293 cells (homogenized cells). The most active compound when tested in intact HEK-293 transfected cells, namely (3α,5α)-3-{[trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl] sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one (15b), shows an IC?? value of 6 nM, this compound is thus eight times more active than our reference compound D-5-2 (IC??=51 nM). This new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile. Compound 15b is thus a good candidate for further in vivo studies on rodents.     

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.     

Structural assessment and identification of 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Communicated by Ramaswamy H. Sarma     

Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17β-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17β-HSD2 inhibitors have been reported. Our previous work led to the identification of phenylbenzenesulfonamides and -sulfonates as new 17β-HSD2 inhibitors by ligand-based pharmacophore modeling and virtual screening. In this study, new molecules representing this scaffold were synthesized and tested in vitro for their 17β-HSD2 activity to derive more profound structure-activity relationship rules.     

Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC₅₀ values in the 100 nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC₅₀ = 114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC₅₀ = 280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.     

Design,synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1

The enzyme 11β-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11β-HSD1 is an attractive intervention strategy and the discovery of novel selective 11β-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11β-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC₅₀ below 400?nM) that were inactive at 1?µM concentration against structurally related enzymes (11β-HSD2, 17β-HSD1 and 17β-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.     

Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11β-hydroxysteroid dehydrogenase type I

Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC(50)<1μM) in a cellular model (3T3L1 adipocytes).     

Synthesis and evaluation of β-carboline derivatives as inhibitors of human immunodeficiency virus

A series of β-carboline derivatives were synthesized by utilizing aromatization and chemoselective alkylation method recently reported from our laboratory. Synthesized derivatives were evaluated for anti-HIV activity in human CD4+ T cell line (CEM-GFP) infected with HIV-1 NL_4.3 virus. 1-Formyl-β-carboline-3-carbxylic acid methyl ester (15) showed inhibition of human immunodeficiency virus at IC₅₀ = 2.9 μM.     

3-Amino-N-adamantyl-3-methylbutanamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitor

Many adamantane derivatives have been demonstrated to function as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. 3-Amino-N-adamantyl-3-methylbutanamide derivatives were optimized by structure-based drug design. Compound 8j exhibited a good in vitro and ex vivo inhibitory activity against both human and mouse 11β-HSD1.     

Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors

Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the ??-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of ??-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K_i values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K_i against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K_i value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K_i value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.     

Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC₅₀ value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.     

Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11β-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.     

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes.In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP⁺. For this compound also the most favourable Docking Score value was obtained.The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.