Category: 936250-20-3

Larsen, Matthew A.; Hartwig, John F. published the artcile< Iridium-Catalyzed C-H Borylation of Heteroarenes: Scope, Regioselectivity, Application to Late-Stage Functionalization, and Mechanism>, Category: pyrazoles-derivatives, the main research area is iridium catalyzed carbon hydrogen borylation heteroarene regioselectivity functionalization mechanism; tetramethylphenanthroline iridium catalyzed heteroarene borylation regioselectivity computational study.

A study on the iridium-catalyzed C-H borylation of heteroarenes is reported. Several heteroarenes containing multiple heteroatoms were amenable to C-H borylation catalyzed by the combination of an iridium(I) precursor and tetramethylphenanthroline. The investigations of the scope of the reaction led to the development of powerful rules for predicting the regioselectivity of borylation, foremost of which is that borylation occurs distal to nitrogen atoms. One-pot functionalizations are reported of the heteroaryl boronate esters formed in situ, demonstrating the usefulness of the reported methodol. for the synthesis of complex heteroaryl structures. Application of this methodol. to the synthesis and late-stage functionalization of biol. active compounds is also demonstrated. Mechanistic studies show that basic heteroarenes can bind to the catalyst and alter the resting state from the olefin-bound complex observed during arene borylation to a species containing a bound heteroarene, leading to catalyst deactivation. Studies on the origins of the observed regioselectivity show that borylation occurs distal to N-H bonds due to rapid N-H borylation, creating an unfavorable steric environment for borylation adjacent to these bonds. Computational studies and mechanistic studies show that the lack of observable borylation of C-H bonds adjacent to basic nitrogen is not the result of coordination to a bulky Lewis acid prior to C-H activation, but the combination of a higher-energy pathway for the borylation of these bonds relative to other C-H bonds and the instability of the products formed from borylation adjacent to basic nitrogen.

Journal of the American Chemical Society published new progress about Boronic acids, esters Role: RCT (Reactant), SPN (Synthetic Preparation), RACT (Reactant or Reagent), PREP (Preparation) (heteroaryl). 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Category: pyrazoles-derivatives.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Gutierrez, Corey D.; Bavetsias, Vassilios; McDonald, Edward published the artcile< ClTi(OiPr)3-Promoted Reductive Amination on the Solid Phase: Combinatorial Synthesis of a Biaryl-Based Sulfonamide Library>, Category: pyrazoles-derivatives, the main research area is combinatorial library biarylsulfonamide preparation; titanium promotor reductive amination aldehyde solid support; sulfonylation resin bound amine; sulfonamide biaryl combinatorial library preparation.

A combinatorial library (9 amines × 7 sulfonyl chlorides × 13 boronic acids = 819 compounds) was produced on solid support in a four-step sequence, i.e., ClTi(OiPr)3-promoted reductive amination, sulfonylation of the resin-bound amine, Suzuki cross-coupling, and acid-mediated cleavage. The library members (e.g. I) were obtained in moderate quantity (1-8 mg) with over 70% of the sampled products greater than 90% pure according to LC-MS anal.

Journal of Combinatorial Chemistry published new progress about Aldehydes Role: CMB (Combinatorial Study), RCT (Reactant), RACT (Reactant or Reagent). 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Category: pyrazoles-derivatives.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Pan, Jinpeng; Yin, Yan; Zhao, Lianhua; Feng, Yangbo published the artcile< Discovery of (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide as potent and isoform selective ROCK2 inhibitors>, Synthetic Route of 936250-20-3, the main research area is ROCK2 inhibitor selectivity methoxychromancarboxylatepyridin phenylamide; Chromans; Computational theoretical studies; Isoform selectivity; ROCK; ROCK inhibitors.

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biol. evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Mol. docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the exptl. bioactivities, and the anal. of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.

Bioorganic & Medicinal Chemistry published new progress about Free energy of binding. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Synthetic Route of 936250-20-3.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Hudson, Liam; Mui, James; Vazquez, Santiago; Carvalho, Diana M.; Williams, Eleanor; Jones, Chris; Bullock, Alex N.; Hoelder, Swen published the artcile< Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept>, Formula: C10H17BN2O2, the main research area is quinazolinone synthesis antitumor SAR ALK2 cancer.

Structure-activity relationship and crystallog. data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chem. modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.

Journal of Medicinal Chemistry published new progress about Activin receptor ACVRLK2 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Formula: C10H17BN2O2.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Fang, Xingang; Yin, Yan; Chen, Yen Ting; Yao, Lei; Wang, Bo; Cameron, Michael D.; Lin, Li; Khan, Susan; Ruiz, Claudia; Schroter, Thomas; Grant, Wayne; Weiser, Amiee; Pocas, Jennifer; Pachori, Alok; Schurer, Stephan; Lo Grasso, Philip; Feng, Yangbo published the artcile< Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors>, Application of C10H17BN2O2, the main research area is tetrahydroisoquinoline derivative rho kinase inhibitor antiglaucoma.

Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochem. and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC50 = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacol. studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.

Journal of Medicinal Chemistry published new progress about Antiglaucoma agents. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Application of C10H17BN2O2.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Gopalsamy, Ariamala; Aulabaugh, Ann E.; Barakat, Amey; Beaumont, Kevin C.; Cabral, Shawn; Canterbury, Daniel P.; Casimiro-Garcia, Agustin; Chang, Jeanne S.; Chen, Ming Z.; Choi, Chulho; Dow, Robert L.; Fadeyi, Olugbeminiyi O.; Feng, Xidong; France, Scott P.; Howard, Roger M.; Janz, Jay M.; Jasti, Jayasankar; Jasuja, Reema; Jones, Lyn H.; King-Ahmad, Amanda; Knee, Kelly M.; Kohrt, Jeffrey T.; Limberakis, Chris; Liras, Spiros; Martinez, Carlos A.; McClure, Kim F.; Narayanan, Arjun; Narula, Jatin; Novak, Jonathan J.; O’Connell, Thomas N.; Parikh, Mihir D.; Piotrowski, David W.; Plotnikova, Olga; Robinson, Ralph P.; Sahasrabudhe, Parag V.; Sharma, Raman; Thuma, Benjamin A.; Vasa, Dipy; Wei, Liuqing; Wenzel, A. Zane; Withka, Jane M.; Xiao, Jun; Yayla, Hatice G. published the artcile< PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease>, Reference of 936250-20-3, the main research area is pf07059013 noncovalent Hb modulator sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult Hb (HbA) that results in sickled Hb (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clin. candidate PF-07059013 (23). The seminal hit mol. was discovered by virtual screening and confirmed through a series of biochem. and biophys. studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-wk multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clin. trials.

Journal of Medicinal Chemistry published new progress about Crystal structure. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Reference of 936250-20-3.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Liu, Dandan; Ge, Huan; Xu, Fangling; Xu, Yufang; Liu, Wenjun; Li, Honglin; Zhu, Lili; Diao, Yanyan; Zhao, Zhenjiang published the artcile< Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors>, Application In Synthesis of 936250-20-3, the main research area is aminopyridine preparation docking antitumor SAR JAK2 inhibitor human.

The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, I exhibited high inhibitory activity against JAK2 with an IC50 of 9 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, resp. Besides, I had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound I had the potential to be developed as a selective JAK2 inhibitor for further study.

Chinese Chemical Letters published new progress about Aminopyridines Role: PAC (Pharmacological Activity), PRP (Properties), RCT (Reactant), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), RACT (Reactant or Reagent), PREP (Preparation), USES (Uses). 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Application In Synthesis of 936250-20-3.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Swain, Nigel. A.; Batchelor, Dave; Beaudoin, Serge; Bechle, Bruce M.; Bradley, Paul A.; Brown, Alan D.; Brown, Bruce; Butcher, Ken J.; Butt, Richard P.; Chapman, Mark L.; Denton, Stephen; Ellis, David; Galan, Sebastien R. G.; Gaulier, Steven M.; Greener, Ben S.; de Groot, Marcel J.; Glossop, Mel S.; Gurrell, Ian K.; Hannam, Jo; Johnson, Matthew S.; Lin, Zhixin; Markworth, Christopher J.; Marron, Brian E.; Millan, David S.; Nakagawa, Shoko; Pike, Andy; Printzenhoff, David; Rawson, David J.; Ransley, Sarah J.; Reister, Steven M.; Sasaki, Kosuke; Storer, R. Ian; Stupple, Paul A.; West, Christopher W. published the artcile< Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7>, Electric Literature of 936250-20-3, the main research area is PF05089771 drug design synthesis NaV17 sodium channel inhibitor pain; diaryl ether aryl sulfonamide preparation sodium channel inhibitor pharmacokinetics.

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and sub-type selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P 450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclin. in vitro properties. Concerns over non-metabolic routes of clearance, variable clearance in pre-clin. species and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clin. pharmacokinetics. The design strategies and results from pre-clin. PK and clin. human microdose PK data are described leading to the discovery of the first sub-type selective NaV1.7 inhibitor clin. candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

Journal of Medicinal Chemistry published new progress about Analgesics. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Electric Literature of 936250-20-3.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

St. Denis, Jeffrey D.; Chessari, Gianni; Cleasby, Anne; Cons, Benjamin D.; Cowan, Suzanna; Dalton, Samuel E.; East, Charlotte; Murray, Christopher W.; OReilly, Marc; Peakman, Torren; Rapti, Magdalini; Stow, Jessie L. published the artcile< X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor>, Product Details of C10H17BN2O2, the main research area is fragment based drug discover electrophilic fragment screening ERK2 ATP.

Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallog. as the primary hit-finding technol. Several fragments were found to have covalently modified the ATP (ATP) binding pocket Cys166 residue. From these hits, 22 (I), a covalent ATP-competitive inhibitor with improved potency (ERK2 IC50 = 7.8 μM), was developed.

Journal of Medicinal Chemistry published new progress about Covalent inhibitors. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Product Details of C10H17BN2O2.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics