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Purity: ≥98%
UAMC00039 dihydrochloride is a novel, potent, reversible and competitive dipeptidyl peptidase II (DPP-II) inhibitor with an IC50 of 0.48 nM. UAMC 00039 dihydrochloride demonstrates selectivity for DPP-II against DPP-9, DPP-8 and DPP-IV (IC50 values are 78.6, 142 and 165 μM, respectively).
| Targets |
Dipeptidyl peptidase II (DPPII) inhibitor (IC50 = 0.48 ± 0.04 nM).
The compound shows high selectivity for DPPII over DPPIV (IC50 = 165 ± 9 µM) and over DPP activity not caused by DPPII or DPPIV (DPP activity in cell homogenates after removal of DPPII and DPPIV by affinity chromatography).[1] |
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| ln Vitro |
DPP activity is not generated by DPPIV or DPPII, as UAMC00039 is extremely selective for DPPII (IC50=0.48±0.04 nM) compared to DPPIV (IC50=165±9 µM). In order to elucidate the role of DPPII and confirm its potential as a therapeutic target, UAMC00039 seems to be a promising tool [1]. The strength of DPPII inhibitors against the enzyme, as well as their capacity to penetrate cells and remain stable in the culture medium, determine their effectiveness in cell culture. For at least 48 hours at 37°C, UAMC00039 remains stable in culture medium and DPPII test buffer. Within a minute, the chemical can penetrate PBMC and block intracellular DPPII activity in a concentration-dependent manner while leaving "non-DPPII" DPP activity unaffected. Over 90% of DPPII activity in PBMC and U937 cells was suppressed by 1 and 100 μM UAMC00039[2].
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| ln Vivo |
In the peripheral organs of rats, mice, and rabbits, dose-dependent inhibition of DPPII but not DPPIV was seen following oral dosing (after intravenous injection). UAMC00039 When taken orally at a dose of 2 mg/kg, the following parameters were evaluated: general behavior, body temperature, respiration, bleeding time, blood pressure, urine output, liver function, fasting blood glucose, and gastric function. Additionally, there were no significant changes in any of the intestinal parameters, such as acidity, peristalsis, and irritation [1].
Upon a single intravenous (IV) bolus administration of UAMC-00039 dihydrochloride (1 µmol/kg) to rabbits, serum DPPII activity fell to less than 5% of the initial value within 15 minutes and normalized after 2 days. A lower dose (0.2 µmol/kg) resulted in slightly less potent inhibition, suggesting dose dependency. Repeated injections after 5 and 40 days resulted in similar profound inhibition and recovery kinetics. DPPIV activity in serum was not inhibited.[1] After oral administration to rats (1 µmol/kg), serum DPPII activity fell to less than 30% of the initial value within 1 hour.[1] Oral administration to mice and rats (up to 5 µmol/kg and 1 µmol/kg, respectively) or IV administration to rabbits (1 µmol/kg) resulted in dose-dependent inhibition of DPPII, but not DPPIV, activity in peripheral organs (kidney, liver, spleen, lung, heart, brain).[1] |
| Enzyme Assay |
DPPII enzyme activity was determined kinetically by measuring the initial velocity of p-nitroaniline release at 405 nm over 10 minutes at 37°C. The assay used Lys-Ala-p-nitroanilide (1 mM) as substrate in 0.1 M cacodylic acid-NaOH buffer (pH 5.5) containing 10 mM EDTA and aprotinin (14 µg/mL).[1]
DPPIV enzyme activity was determined similarly using Gly-Pro-p-nitroanilide (0.5 mM) as substrate in 0.05 M Tris buffer (pH 8.3).[1] One unit of enzyme activity was defined as the amount catalyzing the release of 1 µmol p-nitroaniline per minute under assay conditions.[1] |
| Animal Protocol |
Efficacy and Oral Availability Tests:
Male Swiss mice (~0.023 kg), male Wistar rats (~0.46 kg), and male CLO New Zealand White rabbits (~4.00 kg) were used.[1] For intravenous (IV) administration to rabbits, the inhibitor was administered as a 2 mM solution in 50 mM sodium-phosphate buffer (pH 7.4) at a volume of 0.5 mL/kg.[1] For oral administration to rats, the same 2 mM solution in phosphate buffer was given by gavage at 0.5 mL/kg.[1] For oral administration to mice, the compound was given by gavage as a suspension in 2% Tween 80 at a volume of 10 mL/kg. Mice were fasted for 24 hours before dosing.[1] Blood samples were collected from the auricular artery (rabbits), tail vein (rats), or abdominal vena cava (mice, after anesthesia) at various time points after administration.[1] Animals were euthanized 3-5 hours (rabbits, rats) or 2 hours (mice) after the last dose for tissue collection (kidney, liver, spleen, lung, heart, brain). Tissues were homogenized in PBS containing aprotinin (1%) and octylglucoside (1%), and supernatants were used for enzyme activity assays.[1] Pharmacology and Toxicology Profiling: Male or female ICR mice, Wistar and Long Evans rats, and Duncan Hartley guinea pigs were used.[1] The compound was administered orally at 2 mg/kg (approximately 5 µmol/kg) in a vehicle of 2% Tween 80 (10 mL/kg) on a blind basis in all in vivo assays.[1] For in vitro tissue assays (e.g., cardiac, smooth muscle), the inhibitor was dissolved in DMSO and diluted in the bath to a final concentration of 30 µM (0.1% DMSO).[1] |
| ADME/Pharmacokinetics |
This study confirmed the in vivo efficacy and oral bioavailability of UAMC-00039 dihydrochloride. [1] In rabbits, intravenous injection (1 µmol/kg) rapidly reduced serum DPPII activity (to less than 5% of initial value within 15 minutes). [1] In rats, oral administration (1 µmol/kg) reduced serum DPPII activity (to less than 30% of initial value within 1 hour). [1] Both intravenous (rabbit) and oral (mouse, rat) administration of this compound showed dose-dependent inhibition of DPPII in serum and peripheral organs. [1]
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| Toxicity/Toxicokinetics |
In efficacy and oral bioavailability studies, no acute toxicity was observed in rabbits via intravenous injection and in mice and rats via oral administration at doses up to 5 µmol/kg. [1]
In a comprehensive pharmacological and toxicological screening, oral administration of 2 mg/kg of UAMC-00039 dihydrochloride did not cause any signs of acute toxicity or significant changes in a variety of assessable functions. These functions included general behavior, body temperature, respiration, bleeding time, blood pressure, urine output, liver function, fasting blood glucose, gastrointestinal parameters, analgesia, cholinergic, dopaminergic, serotonergic, adrenergic and other neurotransmitter system functions, and in vitro effects on the heart, smooth muscle and various other tissues at a concentration of 30 µM. [1] |
| References | |
| Additional Infomation |
UAMC-00039 dihydrochloride (N-(4-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butanediamine dihydrochloride) is a potent and highly selective DPPII inhibitor developed as a tool compound to elucidate the physiological function of DPPII and validate its potential as a therapeutic target. [1]
This compound is a γ-amino-substituted analog of 1-[(S)-2,4-diaminobutyryl]piperidine. [1] Its high selectivity for DPPII relative to related enzymes such as DPPIV and DPP8/9 is potentially important for predicting its favorable side effect profile, as other studies have shown that inhibition of DPP8/9 is associated with toxicity. [1] No significant pharmacological effects were observed in extensive screening experiments, suggesting that serious side effects (e.g., cardiovascular side effects) are not expected, which supports its use as a tool compound for further in vivo studies. [1] |
| Molecular Formula |
C16H26CL3N3O
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|---|---|
| Molecular Weight |
382.7561
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| Exact Mass |
381.114
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| CAS # |
697797-51-6
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| PubChem CID |
24757888
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
23
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| Complexity |
313
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CCN(CC1)C(=O)[C@H](CCNCC2=CC=C(C=C2)Cl)N.Cl.Cl
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| InChi Key |
IWXMOQGMIWZNPR-CKUXDGONSA-N
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| InChi Code |
InChI=1S/C16H24ClN3O.2ClH/c17-14-6-4-13(5-7-14)12-19-9-8-15(18)16(21)20-10-2-1-3-11-20;;/h4-7,15,19H,1-3,8-12,18H2;2*1H/t15-;;/m0../s1
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| Chemical Name |
(2S)-2-Amino-4-[[(4-chlorophenyl)methyl]amino]-1-(1-piperidinyl)-1-butanone dihydrochloride
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| Synonyms |
UAMC00039 2HCl, UAMC 00039, UAMC-00039, UAMC 00039 dihydrochloride, UAMC 00039 2HCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ≥ 150 mg/mL (~391.89 mM)
H2O : ~100 mg/mL (~261.26 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (261.26 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6126 mL | 13.0630 mL | 26.1260 mL | |
| 5 mM | 0.5225 mL | 2.6126 mL | 5.2252 mL | |
| 10 mM | 0.2613 mL | 1.3063 mL | 2.6126 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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