Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development
Abstract
:1. Introduction
2. Endogenous Modulation of DDAH Activity
3. Pharmacological Induction of DDAH
4. Pharmacological Inhibition of DDAH
4.1. Substrate-Like Inhibitors
4.1.1. S-Nitroso-l-Homocysteine (HcyNO)
4.1.2. 2-Chloroacetamidine and N-But-3-ynyl-2-chloroacetamidine
4.1.3. (S)-2-Amino-4-(3-Methylguanidino)butanoic Acid Analogues
4.1.4. NG-Substituted-l-Arginine Analogues
4.1.5. NG-(2-Methoxyethyl)-l-Arginine Carboxylate Bioisosteres
4.1.6. N5-(1-Iminoalk(en)yl)-l-Ornithine Derivatives
4.2. Non-Substrate-Like Inhibitors
4.2.1. Pentafluorophenyl (PFP) Sulfonate Esters
4.2.2. Indolylthiobarbituric Acid Derivatives
4.2.3. Ebselen
4.2.4. 4-Hydroxy-2-Nonenal
4.2.5. PD 404182
4.2.6. Proton Pump Inhibitors
4.2.7. 1,2,3-Triazoles
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
DDAH | Dimethylarginine dimethylamino hydrolase |
ADMA | Asymmetric dimethylarginine |
L-NMMA | Monomethyl arginine |
NOS | Nitric oxide synthase |
NO | Nitric oxide |
SDMA | Symmetric dimethylarginine |
PRMTs | Protein arginine methyl transferases |
CAT | Cationic amino acid transporter |
AGXT2 | Alanine-glyoxylate amino transferase 2 |
PKA | Protein kinase A |
Akt | Protein kinase B |
VEGF | Vascular endothelial growth factor |
iNOS | Inducible nitric oxide synthase |
TNF-α | Tumour necrosis factor α |
LDL | Low density lipoprotein |
IL-1β | Interleukin-1β |
AT1-R | Type 1 angiotensin receptor |
DNA | Deoxyribonucleic acid |
FXR | Farnesoid X receptor |
HcyNO | S-Nitroso-l-homocysteine |
NaNO2 | Sodium nitrite |
NaOH | Sodium hydroxide |
HCl | Hydrochloric acid |
Min | Minutes |
Ki | Inhibition constant |
µM | Micromolar |
H2O | Water |
Cys | Cysteine |
His | Histidine |
PaDDAH | Pseudomonas aeruginosa dimethylarginine dimethylamino hydrolase |
PAD | Peptydilarginine deaminase |
NaOMe | Sodium methoxide |
MeOH | Methanol |
AcOH | Acetic acid |
NH4Cl | Ammonium chloride |
PEO | Poly(ethylene oxide) |
DCM | Dichloromethane |
TEA | Triethylamine |
DMAP | 4-Dimethylaminopyridine |
MsCl | Methanesulfonyl chloride |
Et2O | Diethyl ether |
RT | Room temperature |
NaN3 | Sodium azide |
DMF | N,N-Dimethylformamide |
Ph3P | Triphenylphosphine |
4124W | (S)-2-Amino-4-(3-methylguanidino)butanoic acid |
Boc | tert-Butyloxycarbonyl |
M | Molar |
DEAD | Diethyl azodicarboxylate |
THF | Tetrahydrofuran |
DIPEA | N,N-Diisopropylethylamine |
CH3CN | Acetonitrile |
SOCl2 | Thionyl chloride |
SAR | Structure activity relationship |
IC50 | Inhibition constant |
L-257 | NG-(2-Methoxyethyl)-l-arginine |
L-291 | NG-(2-Methoxyethyl)-l-arginine methyl ester |
Orn | Ornithine |
Bu | Butyl |
Z | Carboxybenzyl |
TFMSA | Trifluoromethanesulfonic acid |
TFA | Trifluoroacetic acid |
CDI | 1,1′-Carbonyldiimidazole |
DBU | 1,8-Diazabicyclo[5.4.0]undec-7-ene |
h | Hours |
HATU | 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate |
mM | Millimolar |
DMSO | Dimethyl sulfoxide |
i-BuCOCl | Isobutyl chloroformate |
NH4OH | Ammonium hydroxide |
TFAA | Trifluoroacetic anhydride |
ZnBr2 | Zinc bromide |
NH2OH.HCl | Hydroxylamine hydrochloride |
NaHCO3 | Sodium bicarbonate |
L-VNIO | N5-(1-Imino-3-butenyl)-l-ornithine |
EtOH | Ethanol |
EtOAc | Ethyl acetate |
L-IPO | N5-(1-Iminopropyl)-l-ornithine |
Cl-NIO | N5-(1-Imino-2-chloroethyl)-l-ornithine |
PFP | Pentafluorophenyl |
NaOAc | Sodium acetate |
ADI | Arginine deaminase |
HTS | High throughput screening |
SMTC | S-methyl-l-thiocitrulline |
ESI-MS | Electrospray ionization mass spectrometry |
BuLi | Butyl lithium |
Se | Selenium |
CuBr2 | Copper(II) bromide |
NADPH | Nicotinamide adenine dinucleotide phosphate |
H+/K+ ATPase | Proton/potassium ATPase |
Ca2+ | Calcium 2+ cation |
4-HNE | 4-Hydroxy-2-nonenal |
LOPAC | Library of Pharmacologically Active Compounds |
NaH | Sodium hydride |
CS2 | Carbon disulfide |
BrCN | Cyanogen bromide |
Å | Angstrom |
PPIs | Proton pump inhibitors |
SPR | Surface plasmon resonance |
CM | Carboxymethylated |
(Ph3P)2PdCl2 | Bis(triphenylphosphine)palladium chloride |
CuI | Copper(I) iodide |
TIPS | Triisopropylsilyl |
TMS | Trimethylsilane |
DPPA | Diphenylphosphoryl azide |
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Enzyme | Ki (mM) | Kinact (min−1) |
---|---|---|
PaDDAH | 3.1 ± 0.8 | 1.2 ± 0.1 |
PAD4 | 20 ± 5 | 0.7 ± 0.1 |
Entry | R– | Inhibition at 1 mM (%) | IC50 (μM) | Ki (μM) |
---|---|---|---|---|
1 1 | * CH3OCH2CH2– | 83 | 31 | 13 |
2 1 | CH3NHCH2CH2– | 29 | - | - |
3 1 | (CH3)2NHCH2CH2– | 14 | - | - |
4 1 | CH3SHCH2CH2– | 80 | 408 | - |
5 1 | FCH2CH2– | 67 | 379 | - |
6 1 | BnCH2– | 55 | 866 | - |
7 2 | CH3CH2CH2– | 60 | 283 | 90 |
8 2 | CH2CHCH2– | 70 | 207 | 58 |
9 2 | CH2CHCH2CH2– | 71 | 189 | 57 |
10 2 | CHCCH2– | 83 | 55 | 17 |
11 2 | F3CCH2– | 41 | - | - |
12 2 | O2N– | 6 | - | - |
13 2 | NH2COCH2CH2– | 43 | - | - |
Chemical Number | Chemical Name | Chemical Structure | Enzyme | IC50 (µM) | Ki (µM) | Kinact (min−1) | Reference |
---|---|---|---|---|---|---|---|
(9) | S-Nitroso-l-homocysteine (HcyNO) | | Bovine DDAH-1 | 75 | 690 | 0.38 | [105] |
(11) | 2-Chloroacetamidine | | PaDDAH 1 | - | 3100 | 1.2 | [106] |
(18) | N-But-3-ynyl-2-chloro-acetamidine | | Human DDAH-1 | 350 | - | - | [109] |
(21) | (S)-2-Amino-4-(3-methylguanidino)butanoic acid (4124W) | | Rat DDAH-1 | 416 | - | - | [110] |
(39) | NG-(2-Methoxyethyl)-l-arginine (L-257) | | Human DDAH-1 | 31 2 | 13 2 | - | [112] |
(40) | NG-(2-Methoxyethyl)-l-arginine methyl ester (L-291) | | Rat DDAH-1 | 20 | - | - | [112] |
(44a) | 2-Amino-5-(3-(2-methoxyethyl)guanidino)-N-(methylsulfonyl)-pentanamide (ZST316) | | Human DDAH-1 | 3 | 1 | - | [117] |
(54a) | N5-(1-Imino-3-butenyl)-l-ornithine (L-VNIO) | | Human DDAH-1 | 13 | 2 | - | [114] |
(54b) | N5-(1-Iminopropyl)-l-ornithine (L-IPO) | | Human DDAH-1 | - | 52 | - | [128] |
(54c) | N5-(1-Imino-2-chloroethyl)-l-ornithine (Cl-NIO) | | Human DDAH-1 | - | 1.3 | 0.34 | [129] |
61 | Pentafluorophenyl (PFP) sulfonate esters | | PaDDAH 1 | 16–58 | - | - | [130] |
68a–c | Indolylthiobarbituric acid derivatives | | PaDDAH 1 | 2–17 | - | - | [139] |
(73) | Ebselen | | Human DDAH-1 | 0.33 | - | - | [145] |
(76) | 4-Hydroxy-2-nonenal (4-HNE) | | Human DDAH-1 | 50 | - | - | [167] |
(79) | 6H-6-Imino-(2,3,4,5-tetrahydropyrimido)[1,2-c]-[1,3]benzothiazine (PD 404182) | | Human DDAH-1 | 9 | - | - | [61] |
82a–f | Proton H+/K+ ATPase pump inhibitors (PPIs) | | Human DDAH-1 | 51–63 | - | - | [175] |
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Murphy, R.B.; Tommasi, S.; Lewis, B.C.; Mangoni, A.A. Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development. Molecules 2016, 21, 615. https://doi.org/10.3390/molecules21050615
Murphy RB, Tommasi S, Lewis BC, Mangoni AA. Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development. Molecules. 2016; 21(5):615. https://doi.org/10.3390/molecules21050615
Chicago/Turabian StyleMurphy, Rhys B., Sara Tommasi, Benjamin C. Lewis, and Arduino A. Mangoni. 2016. "Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development" Molecules 21, no. 5: 615. https://doi.org/10.3390/molecules21050615