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[ CAS No. 4595-61-3 ] {[proInfo.proName]}

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Chemical Structure| 4595-61-3
Chemical Structure| 4595-61-3
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Product Citations

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Yuan, Gengyang ; Dhaynaut, Maeva ; Lan, Yu , et al. DOI: PubMed ID:

Abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.

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Hegde, Pooja V. ; Aragaw, Wassihun W. ; Cole, Malcolm S. , et al. DOI: PubMed ID:

Abstract: Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the CoA biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative mols. were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic anal. of these analogs may lead to a next generation POA analog for treating TB.

Keywords: Tuberculosis ; Pyrazinoic acid ; pyrazinamide

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Product Details of [ 4595-61-3 ]

CAS No. :4595-61-3 MDL No. :MFCD00856162
Formula : C5H4N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :IIVUJUOJERNGQX-UHFFFAOYSA-N
M.W : 124.10 Pubchem ID :78346
Synonyms :

Calculated chemistry of [ 4595-61-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 28.99
TPSA : 63.08 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.62
Log Po/w (XLOGP3) : -0.27
Log Po/w (WLOGP) : 0.17
Log Po/w (MLOGP) : -0.85
Log Po/w (SILICOS-IT) : 0.32
Consensus Log Po/w : 0.0

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -0.87
Solubility : 16.9 mg/ml ; 0.136 mol/l
Class : Very soluble
Log S (Ali) : -0.6
Solubility : 31.5 mg/ml ; 0.254 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.98
Solubility : 12.9 mg/ml ; 0.104 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 4595-61-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4595-61-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 4595-61-3 ]

[ 4595-61-3 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 17758-52-0 ]
  • [ 4595-61-3 ]
  • 2
  • [ 4595-61-3 ]
  • [ 42303-42-4 ]
  • [ 845829-97-2 ]
YieldReaction ConditionsOperation in experiment
95% 1a) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylate A solution of 15.74 g (126.9 mmol) pyrimidine-5-carboxylic acid, 43.57 mL (312.6 mmol) triethylamine and 44.61 g (138.9 mmol) TBTU in 460 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (127.3 mmol) ethyl 1-amino-cyclopropane-carboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down and the residue was combined with 200 mL water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol). Yield: 95% of theory C11H13N3O3 (235.24) Rt=1.23 min. method 1
88% 1a) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylateA solution of 6.80 g (54.8 mmol) of pyrimidine-5-carboxylic acid, 18.82 mL (135 mmol) of triethylamine and 19.27 g (60 mmol) of TBTU in 200 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (55 mmol) of ethyl 1-amino-cyclopropanecarboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down, the residue was stirred with 200 mL water and the crude product was extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).Yield: 88% of theoryC11H13N3O3 (235.24)Mass spectrum: [M+H]+=236
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h; Reference Example 3: Preparation of L-[(PYRIMIDIN-5-YLCARBONYL) amino] cyclopropanecarboxylic acid compound with chlorolithium (1: 1). Triethylamine (7.026g, 69.44 mmol) was added to a suspension of 1- (ethoxycarbonyl) cyclopropanaminium chloride (11. 50g, 69. 44 mmol), PYRIMIDINE-5-CARBOXYLIC acid (8.617g, 69.44 mmol), EDC (13.312g, 69.44 mmol), and HOAT (0.945g, 69.44 mmol) in CH2C12 (125mL) and allowed to stir for 16 hours. The reaction was adsorbed onto silica and purified by silica gel chromatography and eluted with ethyl acetate to yield ethyl 1- [ (PYRIMIDIN-5-YLCARBONYL) AMINO]- cyclopropanecarboxylate as a white solid. Low resolution mass spectrometry: (M+H+) = 236.2.
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