51559-52-5

Usage

InChI:InChI=1/C8H13NO3/c1-6(10)7(5-9(2)3)8(11)12-4/h5H,1-4H3

Upstream product

• 463-51-4 Ketene 
• 4637-24-5 N,N-dimethyl-formamide dimethyl acetal 
• 105-45-3 acetoacetic acid methyl ester 

Downstream Products

• 7189-01-7 methyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate 
• 1013914-01-6 methyl 6-(3-fluoro-4-methylphenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate 
• 945715-67-3 C₁₈H₁₆N₂O₃S 
• 945715-66-2 C₁₈H₁₆N₂O₃S 
• 165283-96-5 C₉H₈N₂O₂S 

Relevant academic research and scientific papers

Pharmacological assessment of sepiapterin reductase inhibition on tactile response in the rat

There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect-effect pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.

Design, synthesis and lipid-lowering activities of penipyridone derivatives

On the basis of our earlier discovered natural product penipyridone G with potential lipid-lowering utility, 35 penipyridone derivatives were designed, synthesized and characterized. Based on the oleic acid-induced HepG2 cell lipid accumulation model, compounds 12c, 14, 15f, 15k, 15o, 15p and 16f showed potent lipid-lowering activities among the synthetic compounds at 10 μM. In particular, compounds 4, 15k, 15o showed significant activities on inhibiting lipid accumulation in insulin resistant HepG2 cells, and these three compounds were safe and non-toxic within the concentration range of 400 μM. In comparison, 15o possessed the best lipid-lowering activity. Compared with the vehicle group, the triglyceride inhibition rate of 15o was about 30.2%, and the total cholesterol inhibition rate was about 14.8% at 20 μM, which was equipotent to Simvastatin. Our research indicates that 15o may serve as a promising lead compound for the development of hypolipidemic drugs.

Discovery and Optimization of 2 H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.

MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

HETEROARYL DERIVATIVES AS SEPIAPTERIN REDUCTASE INHIBITORS

Inhibitors of sepiapterin reductase of formula (I) or (I'), wherein the substituents are defined as in the claims, and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.

MUTANT IDH1 INHIBITORS USEFUL FOR TREATING CANCER

Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X1, X2, R1-4 and R13-18 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed.

A facile, regioselective synthesis of pyrazolo[1, 5-a]pyrimidine analogs in the presence of KHSO4 in aqueous media assisted by ultrasound and their anti-inflammatory and anti-cancer activities

Abstract: An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation assisted by KHSO4 in aqueous medium. 3-(4-Methoxyphenyl)-3-o

PYRAZOLOPYRIMIDINES AS INHIBITORS OF GLUCOCORTICOID RECEPTOR TRANSLOCATION

Provided herein are compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of Glucocorticoid Receptor (GR) translocation. Furthermore, the subject compounds and compositions are useful for the treatment of diseases involved in the hypothalamic-pituitary-adrenal (HPA) axis.

SUBSTITUTED PYRIMIDIN-5-CARBOXAMIDES 281

A compound of formula (I): and pharmaceutically-acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11betaHSD1, processes for making them and pharmaceutical compositions comprising them are also described.