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Purity: ≥98%
AZD4017, a nicotinic amide derived carboxylic acid, is a novel, potent, selective and effective inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) in human adipocytes with an IC50 of 7 nM. It exhibits good druglike properties and as a consequence was selected for clinical development. Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. AZD4017 has good potency, selectivity, and pharmacokinetic characteristics.
| Targets |
AZD 4017 displays no detectable activity against glucocorticoid and mineralocorticoid receptors, but demonstrates remarkable selectivity against related enzymes 11-βHSD2, 17β-HSD1, and 17β-HSD3 (all IC50>30 μM). With the exception of cynomolgus monkeys (IC50=0.029 μM), AZD 4017 has markedly reduced activity in various species, despite its high potency against the human version of 11β-HSD1. Furthermore, as adipose tissue is believed to be an important target organ, suppression of 11β-HSD1 activity was assessed in isolated human adipocytes from individuals without diabetes. There is considerable certainty that AZD 4017 is not restricted by adipose tissue because of its acidic nature because it was demonstrated to be a strong inhibitor of this important target tissue (IC50=0.002 μM), which is in good accord with the potency of the enzyme [1].
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| ln Vitro |
AZD 4017 displays no detectable activity against glucocorticoid and mineralocorticoid receptors, but demonstrates remarkable selectivity against related enzymes 11-βHSD2, 17β-HSD1, and 17β-HSD3 (all IC50>30 μM). With the exception of cynomolgus monkeys (IC50=0.029 μM), AZD 4017 has markedly reduced activity in various species, despite its high potency against the human version of 11β-HSD1. Furthermore, as adipose tissue is believed to be an important target organ, suppression of 11β-HSD1 activity was assessed in isolated human adipocytes from individuals without diabetes. There is considerable certainty that AZD 4017 is not restricted by adipose tissue because of its acidic nature because it was demonstrated to be a strong inhibitor of this important target tissue (IC50=0.002 μM), which is in good accord with the potency of the enzyme [1].
AZD4017 potently inhibited human 11β-HSD1 enzyme activity with an IC50 of 7 nM. In human adipocytes isolated from non-diabetic volunteers, AZD4017 inhibited the conversion of cortisone to cortisol with an IC50 of 2 nM, confirming activity in a key target tissue. The compound showed no significant inhibition (<25% at 10 μM) against five major cytochrome P450 enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It was non-mutagenic in a two-strain Ames test and negative in a mouse lymphoma assay. In the hERG IonWorks assay, AZD4017 had an IC50 > 100 μM. It showed good cellular permeability in an MDCK assay with an apparent permeability (Papp A-B) of 29 x 10^-6 cm/s and a low efflux ratio of 0.8. A crystal structure revealed its binding mode: the amide carbonyl interacts with Tyr183, the carboxylate forms a hydrogen bond with the backbone NH of Leu217, and the pyridyl ring is positioned between hydrophobic residues Leu217 and Ala172. [1] |
| ln Vivo |
Only a few preclinical pharmacodynamic evaluations were carried out because of AZD 4017's low efficacy against the mouse enzyme. Increasing the doses further produced a maximal effect of about 70% inhibition at 1500 mg/kg, which is comparable to 10×IC50 in mice. This indicates that AZD 4017 inhibits 11β-HSD1 in this model in a dose-dependent manner [1].
In an ex vivo assay using epididymal adipose tissue from lean mice dosed orally with AZD4017, dose-dependent inhibition of 11β-HSD1 activity was observed. At 1 hour post-dose, 50% inhibition was achieved at 50 mg/kg, corresponding to plasma exposure equivalent to the mouse enzyme IC50. A maximal effect of approximately 70% inhibition was observed at 1500 mg/kg (10 times the mouse enzyme IC50). [1] |
| Enzyme Assay |
The inhibitory activity against 11β-HSD1 was measured using a cortisol competitive homogeneous time-resolved fluorescence (HTRF) assay.
The assay was performed in black 384-well plates containing cortisone, glucose 6-phosphate, NADPH, glucose 6-phosphate dehydrogenase, EDTA, potassium phosphate buffer (pH 7.5), recombinant human (or other species) 11β-HSD1 enzyme, and the test compound. The reaction mixture was incubated at 37°C for 25 minutes to allow enzymatic conversion of cortisone to cortisol. The reaction was stopped by adding a solution containing cortisol-XL665 tracer and an acid. Anti-cortisol cryptate antibody was then added, and after a 2-hour incubation at room temperature, fluorescence emission at 665 nm and 620 nm was measured following excitation at 320 nm using a plate reader. The ratio of fluorescence at 665 nm to 620 nm was calculated and used to determine IC50 values. [1] |
| Cell Assay |
Inhibition of 11β-HSD1 in isolated human adipocytes was assessed.
Subcutaneous adipose tissue was obtained from non-diabetic volunteers, and adipocytes were isolated via collagenase digestion. The isolated adipocytes were incubated in culture medium containing ^3H-cortisone and the test compound for 6 hours at 37°C under 5% CO2. After incubation, the medium was collected, and radiolabeled steroids were extracted using ethyl acetate. The extracted samples were dried, reconstituted, and analyzed by reversed-phase high-performance liquid chromatography (HPLC) using a C18 column with a methanol/water mobile phase. The eluted radioactivity corresponding to cortisone and cortisol was measured using a flow scintillation analyzer to quantify the enzymatic conversion and its inhibition. [1] |
| Animal Protocol |
For the ex vivo pharmacodynamic study in mice, male C57BL/6 mice on a chow diet were dosed by oral gavage with AZD4017 suspended in a hydroxypropyl methylcellulose (HPMC)/Tween formulation.
At 1 hour post-dose, animals were euthanized, blood was collected via cardiac puncture for compound level analysis, and epididymal fat pads were removed and snap-frozen. The adipose tissue was cut into small pieces and incubated in medium containing ^3H-cortisone for 1 hour at 37°C. Following incubation, the medium was processed for steroid extraction and HPLC analysis as described in the cell assay to measure residual 11β-HSD1 activity. [1] For pharmacokinetic studies in mouse, rat, and dog, AZD4017 was administered at doses of 1-3 mg/kg, either as a solution in DMSO/hydroxy-β-cyclodextrin or as a suspension in HPMC/Tween. [1] |
| ADME/Pharmacokinetics |
AZD4017 exhibits high oral bioavailability: >100% in mice and rats (attributable to enterohepatic circulation of the acyl glucuronide metabolite), and 60% in dogs. Medium plasma clearance (Clp): 16 mL/min/kg in mice, 9 mL/min/kg in rats, and 7 mL/min/kg in dogs. Steady-state volume of distribution (Vd_ss): 4.2 L/kg in mice, 2.6 L/kg in rats, and 0.9 L/kg in dogs. Half-life (t1/2): 3.2–4.7 h in mice and rats, and 4.9–6.2 h in dogs. Low plasma protein binding (PPB): 2.9% in mice, 1.8% in rats, and 2.3% in dogs. The human plasma concentration is 0.8%. Water solubility at pH 7.4: 144 μM. The main metabolic pathway in rat, dog, and human hepatocytes is conversion to acyl glucuronide conjugates. Secondary peaks in the pharmacokinetic curves of mice and dogs suggest the presence of enterohepatic circulation. [1]
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| Toxicity/Toxicokinetics |
In male rats, radiolabeled covalent binding studies following oral administration of 20 mg/kg AZD4017 showed no significant covalent binding to plasma or liver proteins (<25 pmol/mg protein at 2 hours, undetectable at 24 hours). No significant induction of cytochrome P450 enzymes was observed in rats one month after administration. The compound was evaluated in guinea pig monophasic action potential (MAP) assays, and no changes in any parameters were observed. The compound exhibited good selectivity for a variety of non-target enzymes and receptors. [1]
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| References | |
| Additional Infomation |
AZD-4017 is currently undergoing clinical trial NCT01173471 (a Phase IIa study evaluating the tolerability, safety, and efficacy of AZD4017 in treating elevated intraocular pressure). AZD4017, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, is a selective, orally bioavailable 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1; 11bHSD1; HSD11B1) inhibitor with potential protective effects. After administration, AZD4017 selectively binds to 11b-HSD1 and inhibits its activity. This prevents cortisol from being converted into the active hormone cortisol, which activates glucocorticoid receptors. By inhibiting cortisol production in metabolic tissues, AZD4017 may suppress adverse metabolic responses induced by exogenous glucocorticoids in these tissues, such as impaired glucose tolerance, hyperinsulinemia, systolic hypertension, increased fat accumulation, muscle atrophy, and skin atrophy. 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) is highly expressed in metabolic tissues such as the liver, skeletal muscle, and adipose tissue. It plays a crucial role in the regeneration of circulating glucocorticoids into active glucocorticoids and regulates cortisol production to activate glucocorticoid receptors. AZD4017 does not inhibit the anti-inflammatory activity of administered glucocorticoids. AZD4017 is an acidic inhibitor found in the 2-thioalkylnicotinamide family of compounds, optimized by introducing a carboxylic acid group to improve its metabolic stability and pharmacokinetic properties. Its high ligand lipophilicity efficiency (LLE = 6.0) indicates an optimal balance between potency and lipophilicity. A stable anhydrous crystalline form has been identified, indicating no significant issues with solid-state development. Based on its potent target inhibition, excellent selectivity, favorable cross-species pharmacokinetic characteristics, and preliminary safety pharmacology results, AZD4017 was selected as a clinical candidate drug for the treatment of metabolic syndrome. [1]
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| Molecular Formula |
C22H33N3O3S
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| Molecular Weight |
419.58100
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| Exact Mass |
419.224
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| Elemental Analysis |
C, 62.98; H, 7.93; N, 10.01; O, 11.44; S, 7.64
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| CAS # |
1024033-43-9
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| PubChem CID |
24946280
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.793
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
29
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| Complexity |
541
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(O)C[C@H]1CN(C2=NC(SCCC)=C(C(NC3CCCCC3)=O)C=C2)CCC1
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| InChi Key |
NCDZABJPWMBMIQ-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C22H33N3O3S/c1-2-13-29-22-18(21(28)23-17-8-4-3-5-9-17)10-11-19(24-22)25-12-6-7-16(15-25)14-20(26)27/h10-11,16-17H,2-9,12-15H2,1H3,(H,23,28)(H,26,27)/t16-/m0/s1
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| Chemical Name |
2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]piperidin-3-yl]acetic acid
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| Synonyms |
AZD4017; AZD-4017; AZD 4017.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~297.92 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3833 mL | 11.9167 mL | 23.8334 mL | |
| 5 mM | 0.4767 mL | 2.3833 mL | 4.7667 mL | |
| 10 mM | 0.2383 mL | 1.1917 mL | 2.3833 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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