MLN-4760 is a novel, potent and selective human angiotensin-converting (ACE2) inhibitor with IC50 of 0.44 nM and with excellent selectivity (>5000-fold) versus related enzymes including human testicular ACE (IC50, >100 μM) and bovine carboxypeptidase A (CPDA; IC50, 27 μM). In huMNCs, MLN-4760-B detected 63% ACE2 with 28-fold selectivity over ACE.
Physicochemical Properties
| Molecular Formula | C19H23CL2N3O4 |
| Molecular Weight | 428.3096 |
| Exact Mass | 427.107 |
| CAS # | 305335-31-3 |
| Related CAS # | (R)-MLN-4760;305335-29-9 |
| PubChem CID | 448281 |
| Appearance | Off-white to light yellow solid powder |
| LogP | 3.713 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 28 |
| Complexity | 527 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | CC(C)C[C@@H](C(=O)O)N[C@@H](CC1=CN=CN1CC2=CC(=CC(=C2)Cl)Cl)C(=O)O |
| InChi Key | NTCCRGGIJNDEAB-IRXDYDNUSA-N |
| InChi Code | InChI=1S/C19H23Cl2N3O4/c1-11(2)3-16(18(25)26)23-17(19(27)28)7-15-8-22-10-24(15)9-12-4-13(20)6-14(21)5-12/h4-6,8,10-11,16-17,23H,3,7,9H2,1-2H3,(H,25,26)(H,27,28)/t16-,17-/m0/s1 |
| Chemical Name | (2S)-2-[[(2S)-3-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]-1-hydroxy-1-oxopropan-2-yl]amino]-4-methylpentanoic acid |
| Synonyms | MLN-4760 MLN 4760 MLN4760. |
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), 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) |
Biological Activity
| ln Vitro | When compared to similar enzymes such as human testicular ACE (IC50, >100 μM) and bovine carboxypeptidase A (CPDA; IC50, 27), MLN-4760 exhibits superior performance as a strong and selective inhibitor of human ACE2 (IC50, 0.44 nM) with excellent selectivity (>5000x) micron) [1]. In rhACE2, MLN-4760 efficiently prevents 7-Mca-YVADAPK(Dnp) from being cleaved. MLN-4760 had a pIC50 of 8.5±0.1 for rhACE2 and 4.4±0.2 for rhACE. Additionally, in mouse heart and mononuclear cells (MNC), MLN-4760 demonstrated pIC50 values of 4.7±0.1, 6.9±0.1 for rhACE2 and 4.4±0.1, 6.2±0.1 for ACE [2]. |
| ln Vivo | Although MLN-4760 (100 μM, intracerebroventricular infusion for five days) does not significantly increase infarct volume, it significantly affects neurological function at four hours and three days following stroke [3]. |
| References |
[1]. Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. J Am Chem Soc. 2002 Oct 9;124(40):11852-3. [2]. Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells. Eur J Pharmacol. 2016 Mar 5;774:25-33. [3]. Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. Hypertension. 2015 Jul;66(1):141-8. |
| Additional Infomation |
MLN-4760 is a L-histidine derivative that is L-histidine in which a hydrogen of the primary amino group is substituted by a (1S)-1-carboxy-3-methylbutyl group and the ring NH group is substituted by a 3,5-dichlorobenzyl group. It is a potent and selective human angiotensin-converting enzyme 2 (ACE2) inhibitor (IC50 = 0.44 nM) which was in clinical development for the treatment of ulcerative colitis. It has a role as an anti-inflammatory agent and an EC 3.4.17.23 (angiotensin-converting enzyme 2) inhibitor. It is a L-histidine derivative, a dichlorobenzene and a L-leucine derivative. ORE1001 has been used in trials studying the treatment of Mild to Moderate Ulcerative Colitis. It is an ACE2 inhibitor. |
Solubility Data
| Solubility (In Vitro) |
H2O : ~100 mg/mL (~233.48 mM) DMSO : ~50 mg/mL (~116.74 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.84 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 25.0 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: ≥ 2.5 mg/mL (5.84 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 25.0 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 3: ≥ 2.5 mg/mL (5.84 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 25.0 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 | 2.3348 mL | 11.6738 mL | 23.3476 mL | |
| 5 mM | 0.4670 mL | 2.3348 mL | 4.6695 mL | |
| 10 mM | 0.2335 mL | 1.1674 mL | 2.3348 mL |