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| Targets |
INCB-13739 targets 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1), a key enzyme that appears to be critical to the development of type 2 diabetes. 11β-HSD1 converts inactive cortisone into the potent biologically active hormone cortisol intracellularly within several tissues, including adipose tissue and liver. By selectively inhibiting 11β-HSD1, INCB-13739 reduces local glucocorticoid amplification without disrupting systemic cortisol homeostasis. The compound exhibits >1000-fold selectivity over the type 2 isozyme (11β-HSD2), mineralocorticoid receptor (MR), and glucocorticoid receptor (GR), making it a highly specific tool for studying 11β-HSD1 biology.
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| ln Vitro |
For 11β-HSD2, mineralocorticoid receptor (MR), and glucocorticoid receptor (GR), INCB13739 exhibits >1000-fold selectivity [1].
INCB-13739 demonstrates potent enzymatic inhibition with IC50 values of 3.2 nM against recombinant 11β-HSD1 and 1.1 nM in human peripheral blood mononuclear cells (PBMC). It shows >1000-fold selectivity over 11β-HSD2 and steroid receptors. The compound completely inhibits the production of intra-adipose and intra-hepatic cortisol by 11β-HSD1 while maintaining normal systemic cortisol levels. This tissue-specific inhibition profile makes it a valuable tool for dissecting the role of local glucocorticoid production in metabolic diseases. |
| ln Vivo |
INCB13739 (oral) is efficiently distributed in adipose tissue and inhibits 11β-HSD1 activity by >90% for at least 24 hours after administration [1]. INCB13739 (3 mg/kg IV; 10 mg/kg PO; once) demonstrated good oral bioavailability in both rats and cynomolgus monkeys [1]. Pharmacokinetic parameters of INCB13739 in rats [1]. IV (3 mg/kg) PO (10 mg/kg) Cmax (μM) 6.46 ± 2.41 AUC0-24 (ng/mL*h) 11.2 ± 3.27 t1/2 (h) 1.4 ± 0.2 1.2 ± 0.3 CL ((L /h)/kg) 1.0 ± 0.2 Vdss (L/kg) 1.6 ± 0.5 F (%) 51 ± 15
In vivo, INCB-13739 (oral) is efficiently distributed in adipose tissue and inhibits 11β-HSD1 activity by >90% for at least 24 hours after administration. The compound demonstrates significant efficacy in preclinical models, including improved hepatic and peripheral insulin sensitivity with a satisfactory reduction in fasting plasma glucose and cholesterol. In a 12-week dose-ranging study in patients with type 2 diabetes inadequately controlled by metformin monotherapy, INCB-13739 added to ongoing metformin therapy was efficacious, showing significant HbA1c reduction (−0.6%), fasting plasma glucose reduction (−24 mg/dL), and HOMA-IR reduction (−24%) versus placebo. Dose-dependent weight loss, decrease in triglyceride levels, and improvement in blood pressure were also observed. |
| Enzyme Assay |
In vitro enzyme assays for 11β-HSD1 inhibition are used to characterize INCB-13739's activity. The enzyme is incubated with varying concentrations of the compound and cortisone substrate, and the conversion to cortisol is measured by HPLC, mass spectrometry, or immunoassay. IC50 values of 3.2 nM (enzymatic) and 1.1 nM (PBMC) are determined from dose-response curves. Selectivity is assessed by testing the compound against 11β-HSD2, mineralocorticoid receptor, and glucocorticoid receptor, showing >1000-fold selectivity. These assays confirm the compound's potency and specificity as an 11β-HSD1 inhibitor.
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| Cell Assay |
Cell-based assays for INCB-13739 are conducted in primary cells such as human PBMCs or adipocytes. Cells are treated with the compound at various concentrations and stimulated with cortisone. Cortisol production is measured by ELISA or LC-MS/MS. The compound demonstrates IC50 = 1.1 nM in PBMC assays. In adipocyte cultures, INCB-13739 inhibits the conversion of cortisone to cortisol, reducing local glucocorticoid activity and improving insulin sensitivity markers. These cell-based assays confirm the compound's tissue-specific inhibition of 11β-HSD1 activity and its potential to modulate metabolic functions.
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| Animal Protocol |
Animal/Disease Models: Rat, cynomolgus monkey[1]
Doses: 3 mg/kg (IV), 10 mg/ kg (PO) Route of Administration: IV and PO, once (pharmacokinetic/PK/PK analysis) Experimental Results: Demonstrated good oral administration in both rats (F%=51 ± 15%) and cynomolgus monkeys (F%=43%) bioavailability. In vivo animal experiments with INCB-13739 have been conducted in rats and cynomolgus monkeys. In pharmacokinetic studies, the compound was administered at 3 mg/kg IV and 10 mg/kg PO. In efficacy studies, oral administration of INCB-13739 in rodent models of type 2 diabetes and obesity demonstrates improved glycemic control, insulin sensitivity, and reduced body weight. Tissue distribution studies show efficient delivery to adipose tissue with >90% inhibition of 11β-HSD1 activity for at least 24 hours post-administration. These studies support the compound's mechanism of action and therapeutic potential for metabolic disorders. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of INCB-13739 demonstrate good oral bioavailability in both rats (F% = 51 ± 15%) and cynomolgus monkeys (F% = 43%). In rats, IV administration (3 mg/kg) shows: Cmax = 6.46 ± 2.41 μM, AUC0-24 = 11.2 ± 3.27 ng/mL*h, t1/2 = 1.4 ± 0.2 h, CL = 1.0 ± 0.2 (L/h)/kg, and Vdss = 1.6 ± 0.5 L/kg. Oral administration (10 mg/kg) shows t1/2 = 1.2 ± 0.3 h. The compound is efficiently distributed in adipose tissue and inhibits 11β-HSD1 activity by >90% for at least 24 hours after administration. Solubility: DMSO ~125 mg/mL (~267.37 mM). Storage: powder at -20°C for 3 years; in solvent at -80°C for 6 months or -20°C for 1 month.
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| Toxicity/Toxicokinetics |
Safety data from clinical trials indicate that INCB-13739 added to ongoing metformin therapy was well-tolerated in patients with type 2 diabetes. The compound's >1000-fold selectivity over 11β-HSD2, mineralocorticoid receptor, and glucocorticoid receptor minimizes off-target effects. Because it completely inhibits intra-adipose and intra-hepatic cortisol production while maintaining normal systemic cortisol levels, it avoids disrupting the hypothalamic-pituitary-adrenal (HPA) axis. However, comprehensive toxicology data are limited in publicly available sources. The compound is for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling INCB-13739.
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| References | |
| Additional Infomation |
INCB13739 is a novel drug under development for the treatment of type 2 diabetes. It is an oral, small-molecule 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1) inhibitor. 11β-HSD1 is an enzyme that plays a key role in the development and progression of type 2 diabetes.
Drug Indications Investigated for the treatment and prevention of type 2 diabetes. Mechanism of Action INCB13739 is an 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1) inhibitor. 11β-HSD1 is an enzyme that plays a key role in the development and progression of type 2 diabetes. INCB13739 completely inhibits 11β-HSD1-mediated cortisol production in adipose tissue and liver, while maintaining normal systemic cortisol levels, which is essential for immune function and stress response. Pharmacodynamics 11β-HSD1 is an enzyme that converts cortisol into the potent bioactive hormone cortisol. This conversion occurs intracellularly in several key metabolic tissues, including the liver, adipose tissue, muscle, and pancreas. As an antagonist of insulin action, cortisol has been hypothesized to be associated with 11β-HSD1-mediated cortisol production in humans and type 2 diabetes. INCB13739 inhibits 11β-HSD1 and may have broad effects on a variety of symptoms in patients with type 2 diabetes. INCB-13739 has CAS number 869974-19-6, molecular formula C28H25N3O4, and molecular weight 467.52. IUPAC name: N-methyl-5-[4-[1-[(1R)-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-1'-carbonyl]cyclopropyl]phenyl]pyridine-2-carboxamide. Synonyms: INCB13739. The compound is an orally active, potent, selective, and tissue-specific 11β-HSD1 inhibitor with IC50 values of 3.2 nM (enzymatic) and 1.1 nM (PBMC). It was developed for type 2 diabetes mellitus (T2DM) and obesity research. The compound has been evaluated in Phase 2 clinical trials and demonstrated significant HbA1c reduction (−0.6%), FPG reduction (−24 mg/dL), and HOMA-IR reduction (−24%) versus placebo. Key publication: Rosenstock J, et al. Diabetes Care. 2010;33(7):1516-1522. Purity: ≥98%. Not approved for clinical use; for research purposes only. |
| Molecular Formula |
C28H25N3O4
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| Molecular Weight |
467.52
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| Exact Mass |
467.184
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| CAS # |
869974-19-6
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| PubChem CID |
66662059
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
35
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| Complexity |
864
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1C=CC=C2C=1C(=O)O[C@@]12CCN(C1)C(=O)C1(CC1)C1C=CC(C2=CN=C(C(NC)=O)C=C2)=CC=1
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| InChi Key |
BDQCDIWFPIDPQU-NDEPHWFRSA-N
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| InChi Code |
InChI=1S/C28H25N3O4/c1-29-24(32)23-11-8-19(16-30-23)18-6-9-20(10-7-18)27(12-13-27)26(34)31-15-14-28(17-31)22-5-3-2-4-21(22)25(33)35-28/h2-11,16H,12-15,17H2,1H3,(H,29,32)/t28-/m0/s1
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| Chemical Name |
N-methyl-5-[4-[1-[(1R)-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-1'-carbonyl]cyclopropyl]phenyl]pyridine-2-carboxamide
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| Synonyms |
INCB13739; INCB-13739; INCB 13739; 869974-19-6; 160R8ZBH0X; N-methyl-5-[4-[1-[(1R)-3-oxospiro[2-benzofuran-1,3'-pyrrolidine]-1'-carbonyl]cyclopropyl]phenyl]pyridine-2-carboxamide;
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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 (~267.4 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.45 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 (4.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1389 mL | 10.6947 mL | 21.3895 mL | |
| 5 mM | 0.4278 mL | 2.1389 mL | 4.2779 mL | |
| 10 mM | 0.2139 mL | 1.0695 mL | 2.1389 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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