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MLN-4760

Names

[ CAS No. ]:
305335-31-3

[ Name ]:
MLN-4760

[Synonym ]:
(S,S)-2-{1-CARBOXY-2-[3-(3,5-DICHLORO-BENZYL)-3H-IMIDAZOL-4-YL]-ETHYLAMINO}-4-METHYL-PENTANOIC ACID
MLN-4760
UNII-4LD0ZHV25K
XX5
(2S)-2-[[(2S)-3-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]-1-hydroxy-1-oxopropan-2-yl]amino]-4-methylpentanoic acid

Biological Activity

[Description]:

MLN-4760 is a potent and selective human ACE2 inhibitor (IC50, 0.44 nM), with excellent selectivity (>5000-fold) versus related enzymes including human testicular ACE (IC50, >100 μM) and bovine carboxypeptidase A (CPDA; IC50, 27 μM).

[Related Catalog]:

Signaling Pathways >> Metabolic Enzyme/Protease >> Angiotensin-converting Enzyme (ACE)
Research Areas >> Cardiovascular Disease

[Target]

IC50: 0.44 nM (Human ACE2), 27 μM (Bovine carboxypeptidase A)[1]


[In Vitro]

MLN-4760 is a potent and selective human ACE2 inhibitor (IC50, 0.44 nM), with excellent selectivity (>5000-fold) versus related enzymes human testicular ACE (IC50, >100 μM) and bovine carboxypeptidase A (CPDA; IC50, 27 μM)[1]. MLN-4760 effectively quenches cleavage of the 7-Mca-YVADAPK(Dnp) in rhACE2. MLN-4760 shows pIC50 at rhACE2 of 8.5±0.1 and at rhACE of 4.4±0.2. MLN-4760 also shows pIC50 at rhACE2 of 4.7±0.1, 6.9±0.1 and at ACE of 4.4±0.1, 6.2±0.1 in murine heart and mononuclear cells (MNCs), resepctively[2].

[In Vivo]

MLN-4760 (100 μM, intracerebroventricular infusion for five days) significantly worsens neurological function at 4 h and 3 d post-stroke without significantly increasing infarct volume[3].

[Animal admin]

Rats[3] In a related experiment to evaluate the role of central ACE2 in stroke, randomly assigned rats (n = 16) are treated centrally for five days prior to and three days after stroke with the ACE2 inhibitor MLN-4760 (100 μM infused at a rate of 0.5 μL/h) or sterile saline (0.9%) via intracerebroventricular infusion. Following endothelin-1 MCAO, neurological function is assessed at 4 h, 1 d, and 3 d, and brains are harvested at 3 d post-stroke for infarct volume analysis as above[3].

[References]

[1]. Dales NA, et al. 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]. Joshi S, et al. 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]. Bennion DM, et al. Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. Hypertension. 2015 Jul;66(1):141-8.


[Related Small Molecules]

Angiotensin I/II (1-7) trifluoroacetate salt | Captopril | Enalapril maleate | Perindopril erbumine | Lisinopril diydrate | Phosphoramidon disodium salt | Trandolapril | Fosinopril sodium | Quinapril hydrochloride | Ramipril | Cilazapril Monohydrate | Enalaprilat Dihydrate | omapatrilat | Temocapril (hydrochloride) | Hemorphin-7

Chemical & Physical Properties

[ Molecular Formula ]:
C19H23Cl2N3O4

[ Molecular Weight ]:
428.31000

[ Exact Mass ]:
427.10700

[ PSA ]:
104.45000

[ LogP ]:
3.71370


Related Compounds