MK-0429 is a compound that was originally developed as a selective and potent αvβ3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. MK-0429 is an equipotent pan-inhibitor of multiple av integrins. MK-0429 dose-dependently inhibited podocyte motility and also suppressed TGF-β-induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK-0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.
Physicochemical Properties
| Molecular Formula | C23H29N5O4 | |
| Molecular Weight | 439.51 | |
| Exact Mass | 439.221 | |
| CAS # | 227963-15-7 | |
| Related CAS # | 477841-10-4 (5 hydrate);227963-15-7;477841-08-0 (2 hydrate);477841-09-1 (4 hydrate); 1125471-59-1 (0.5 hydrate); | |
| PubChem CID | 9853559 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 699.0±55.0 °C at 760 mmHg | |
| Flash Point | 376.5±31.5 °C | |
| Vapour Pressure | 0.0±2.3 mmHg at 25°C | |
| Index of Refraction | 1.606 | |
| LogP | 2.9 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 9 | |
| Heavy Atom Count | 32 | |
| Complexity | 650 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | COC1=NC=C(C=C1)[C@H](CC(=O)O)N2CCN(C2=O)CCCC3=NC4=C(CCCN4)C=C3 |
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| InChi Key | HGFOOLONGOBCMP-IBGZPJMESA-N | |
| InChi Code | InChI=1S/C23H29N5O4/c1-32-20-9-7-17(15-25-20)19(14-21(29)30)28-13-12-27(23(28)31)11-3-5-18-8-6-16-4-2-10-24-22(16)26-18/h6-9,15,19H,2-5,10-14H2,1H3,(H,24,26)(H,29,30)/t19-/m0/s1 | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vivo | MK-0429 decreases the size and growth of metastatic tumor colonies in the lungs when taken orally twice daily for two weeks at a dose of 100 or 300 mg/kg. MK-0429 is safe and efficient in lowering the metastasis of lung melanoma [1]. |
| Animal Protocol |
Animal/Disease Models: B6D2F1 hybrid female mice [2] Doses: 100 or 300 mg/kg Route of Administration: Orally, twice (two times) daily (bid), 2 weeks Experimental Results: MK-0429 at 100 and 300 mg/kg will metastasize The number of tumor colonies was diminished compared with vehicle, and the tumor area was diminished by 64% and 57% respectively at high doses [2]. |
| ADME/Pharmacokinetics |
Metabolism / Metabolites MK-429 has known human metabolites that include 3-[3-[3-(7-hydroxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-2-oxoimidazolidin-1-yl]-3-(6-oxo-1H-pyridin-3-yl)propanoic acid, 3-(6-Oxo-1H-pyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propanoic acid, and 3-[3-[3-(5-hydroxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-2-oxoimidazolidin-1-yl]-3-(6-oxo-1H-pyridin-3-yl)propanoic acid. |
| References |
[1]. Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. J Med Chem. 2003 Oct 23;46(22):4790-8. [2]. Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis. Oncol Rep. 2015 Jun;33(6):2737-45. [3]. An integrin antagonist (MK-0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model. Pharmacol Res Perspect. 2017 Oct;5(5):e00354. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.62 mg/mL (5.96 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 (4.73 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 3: ≥ 2.08 mg/mL (4.73 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. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.73 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 corn oil and mix evenly. Solubility in Formulation 5: 7.14 mg/mL (16.25 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2753 mL | 11.3763 mL | 22.7526 mL | |
| 5 mM | 0.4551 mL | 2.2753 mL | 4.5505 mL | |
| 10 mM | 0.2275 mL | 1.1376 mL | 2.2753 mL |