Category: 763120-58-7

Giordanetto, Fabrizio published the artcileDiscovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance, Application of 1H-Pyrazole-4-boronic acid, the publication is Bioorganic & Medicinal Chemistry Letters (2012), 22(21), 6671-6676, database is CAplus and MEDLINE.

Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favorable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Addnl., due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Application of 1H-Pyrazole-4-boronic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Bardhan, Sujata published the artcileHeteroaryl ethers by oxidative palladium catalysis of pyridotriazol-1-yloxy pyrimidines with arylboronic acids, Formula: C3H5BN2O2, the publication is Organic Letters (2009), 11(12), 2511-2514, database is CAplus and MEDLINE.

The oxidative palladium-catalyzed cross-coupling of pyrimidines containing pyridotriazol-1-yloxy (OPt) as either a urea or an amide functional group with arylboronic acids in the presence of Cs₂CO₃ in DME containing 0.6-1.0% H₂O is described for the preparation of heteroaryl ethers. The bromo substitution in the case of 3-(5-bromo-pyrimidin-2-yloxy)-3H-[1,2,3]triazolo[4,5-b]pyridine could serve as a handle for further elaborations such as Suzuki coupling for attaching varied aryl groups.

Organic Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Formula: C3H5BN2O2.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Pham, Thanh Truc published the artcileNovel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei, Category: pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry Letters (2017), 27(16), 3629-3635, database is CAplus and MEDLINE.

In 2014, a published report of the high-throughput screen of >42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, the authors selected NEU-<0001101≥(1) for hit-to-lead optimization. Through the authors’ preliminary compound synthesis and SAR studies, the authors confirmed the previously reported activity of 4-phenyl-6-(pyridin-4-yl)quinazolin-2(1H)-one in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 4-phenyl-6-(pyridin-4-yl)quinazolin-2(1H)-one. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 4-phenyl-6-(pyridin-4-yl)quinazolin-2(1H)-one , while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Category: pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Liu, Qingsong published the artcileDiscovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer, Name: 1H-Pyrazole-4-boronic acid, the publication is Journal of Medicinal Chemistry (2011), 54(5), 1473-1480, database is CAplus and MEDLINE.

The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chem. effort led to the discovery of an improved mTOR inhibitor 3 (Torin2, I), which possesses an EC₅₀ of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC₅₀: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1.

Journal of Medicinal Chemistry published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Name: 1H-Pyrazole-4-boronic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Burdick, Daniel J. published the artcileFragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors, Category: pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry Letters (2015), 25(21), 4728-4732, database is CAplus and MEDLINE.

A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine (compound 1) in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole mol. adjacent to (1) suggested a direction for fragment expansion. Structure-based core hopping applied to (1) led to 5H-pyrrolo[3,2-b]pyrazine that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core (I) was quickly optimized to 7-(1-benzyl-1H-pyrazol-4-yl)-2-(pyridin-4-yl)-5H-pyrrolo[3,2-b]pyrazine (compound 39) resulting in a greater than 6600-fold improvement in potency.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Category: pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Gu, Zheng-Song published the artcileSynthesis and antidepressant effect of novel aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT_1A/5-HT₇, Category: pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry Letters (2019), 29(23), 126703, database is CAplus and MEDLINE.

A series of novel aralkyl piperazine and piperidine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT_1A/5-HT₇ receptors affinities activity. Antidepressant activities in vivo of the selective compound were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compound 19a (I) exhibited high affinities for the 5-HT_1A/5-HT₇ receptors (5-HT_1A, K_i = 12 nM; 5-HT₇, K_i = 3.2 nM) coupled with potent serotonin reuptake inhibition (IC₅₀ = 14 nM) and showed a marked antidepressant-like effect in the FST and TST models.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Category: pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Yang, Bin published the artcileAdventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors, Synthetic Route of 763120-58-7, the publication is Journal of Medicinal Chemistry (2018), 61(3), 1061-1073, database is CAplus and MEDLINE.

Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small mol. CHK1 inhibitors from different chem. scaffolds have been developed and evaluated in clin. trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramol. noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramol. hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

Journal of Medicinal Chemistry published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C11H12O4, Synthetic Route of 763120-58-7.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Liang, Jun published the artcileLead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors, Synthetic Route of 763120-58-7, the publication is Journal of Medicinal Chemistry (2013), 56(11), 4521-4536, database is CAplus and MEDLINE.

Herein the authors report the authors’ lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead mol. 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzamide. The authors used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzamide. Further optimization eventually led to 2-Chloro-4-cyano-6-fluoro-N-(2-((1R,2R)-2-fluorocyclopropanecarboxamido)pyridin-4-yl)benzamide that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, 2-Chloro-4-cyano-6-fluoro-N-(2-((1R,2R)-2-ffluorocyclopropanecarboxamido)pyridin-4-yl)benzamide showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

Journal of Medicinal Chemistry published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Synthetic Route of 763120-58-7.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Tarr, James C. published the artcileTargeting Selective Activation of M₁ for the Treatment of Alzheimer’s Disease: Further Chemical Optimization and Pharmacological Characterization of the M₁ Positive Allosteric Modulator ML169, Computed Properties of 763120-58-7, the publication is ACS Chemical Neuroscience (2012), 3(11), 884-895, database is CAplus and MEDLINE.

The M₁ muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer’s disease (AD) and schizophrenia. Moreover, M₁ interacts with BACE1 and regulates its proteasomal degradation, suggesting selective M₁ activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M₁ selective pos. allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analog libraries and probing novel scaffolds. We were able to identify several analogs that possessed submicromolar potency, with our best example displaying an EC₅₀ of 310 nM. The new compounds maintained complete selectivity for the M₁ receptor over the other subtypes (M₂-M₅), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogs were able to potentiate CCh-mediated non-amyloidogenic APPα release, further strengthening the concept that M₁ PAMs may afford a disease-modifying role in the treatment of AD.

ACS Chemical Neuroscience published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C9H5ClO2, Computed Properties of 763120-58-7.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Lizarzaburu, Mike published the artcileDiscovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus, Quality Control of 763120-58-7, the publication is Bioorganic & Medicinal Chemistry Letters (2012), 22(18), 5942-5947, database is CAplus and MEDLINE.

N-alkylphenylalaninamides of pyridinylphenyl- and oxobipyridinylamines such as I were prepared as GPR142 agonists for potential use as antidiabetic agents for type 2 diabetes and tested for their agonism of GPR142 in vitro and in human plasma and their inhibition of cytochrome P 450 enzymes such as isoforms 3A4 and 2D6. Optimization of the original lead compound gave agonists 90 times more potent against human GPR142. Inhibition of cytochrome P 450 isoforms 3A4 and 2D6 was reduced by increasing the polarity of the biarylamine moiety. The pharmacokinetics of I and a thiazolylmethyl phenylalaninamide of an aminopyridinylbenzoate were determined in rats.

Bioorganic & Medicinal Chemistry Letters published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Quality Control of 763120-58-7.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics