Day: October 12, 2022

Large, Jonathan M.; Osborne, Simon A.; Smiljanic-Hurley, Ela; Ansell, Keith H.; Jones, Hayley M.; Taylor, Debra L.; Clough, Barbara; Green, Judith L.; Holder, Anthony A. published the artcile< Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues>, Formula: C15H19BN2O2, the main research area is imidazopyridazine inhibitor preparation antimalarial Plasmodium kinase inhibitor; Calcium-dependent protein kinase 1; Imidazopyridazine; Malaria; Plasmodium falciparum; SAR.

The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogs thus provide a credible addnl. route to further development of the series.

Bioorganic & Medicinal Chemistry Letters published new progress about Antimalarials. 1002334-12-4 belongs to class pyrazoles-derivatives, and the molecular formula is C15H19BN2O2, Formula: C15H19BN2O2.

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

Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon; Brooun, Alexei; Burke, Benjamin J.; Collins, Michael R.; Cui, J. Jean; Deal, Judith G.; Deng, Ya-Li; Dinh, Dac; Engstrom, Lars D.; He, Mingying; Hoffman, Jacqui; Hoffman, Robert L.; Huang, Qinhua; Kania, Robert S.; Kath, John C.; Lam, Hieu; Lam, Justine L.; Le, Phuong T.; Lingardo, Laura; Liu, Wei; McTigue, Michele; Palmer, Cynthia L.; Sach, Neal W.; Smeal, Tod; Smith, Graham L.; Stewart, Albert E.; Timofeevski, Sergei; Zhu, Huichun; Zhu, Jinjiang; Zou, Helen Y.; Edwards, Martin P. published the artcile< Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations>, Reference of 1046832-21-6, the main research area is PF06463922 preparation macrocyclic ALK inhibitor antitumor.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-pos. non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and phys.-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clin. reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 1046832-21-6 belongs to class pyrazoles-derivatives, and the molecular formula is C11H19BN2O2, Reference of 1046832-21-6.

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

Garcia da Silva, Artur Christian; Rodrigues, Bruna dos Santos; Andrade, Wanessa Machado; Marques dos Santos, Thais Rosa; de Carvalho, Flavio Silva; Sanz, German; Vaz, Boniek G.; Liao, Luciano M.; Menegatti, Ricardo; Valadares, Marize Campos published the artcile< Antiangiogenic and antitumoral activity of LQFM126 prototype against B16F10 melanoma cells>, Computed Properties of 13788-92-6, the main research area is Nutlin analog antiangiogenic antitumoral agent melanoma cell; Antitumor drugs; Apoptosis; LQFM126; Melanoma; Molecular simplification; Nutlins.

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through mol. simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Addnl., LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.

Chemico-Biological Interactions published new progress about Angiogenesis. 13788-92-6 belongs to class pyrazoles-derivatives, and the molecular formula is C9H7BrN2, Computed Properties of 13788-92-6.

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

Bagal, Sharan K.; Gregson, Clare; O Donovan, Daniel H.; Pike, Kurt G.; Bloecher, Andrew; Barton, Peter; Borodovsky, Alexandra; Code, Erin; Fillery, Shaun M.; Hsu, Jessie Hao-Ru; Kawatkar, Sameer P.; Li, Chengzhi; Longmire, David; Nai, Youfeng; Nash, Samuel C.; Pike, Andrew; Robinson, James; Read, Jon A.; Rawlins, Phillip B.; Shen, Minhui; Tang, Jia; Wang, Peng; Woods, Haley; Williamson, Beth published the artcile< Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase>, Safety of 1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the main research area is heterocyclic nitrogen analog preparation antitumor SAR enzyme inhibitor.

In this paper the discovery of potent and orally bioavailable EED ligands with good solubilities was disclosed. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.

Journal of Medicinal Chemistry published new progress about Antiproliferative agents. 1046832-21-6 belongs to class pyrazoles-derivatives, and the molecular formula is C11H19BN2O2, Safety of 1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

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

Chen, Deheng; Lu, Tian; Yan, Ziqin; Lu, Wenchao; Zhou, Feilong; Lyu, Xilin; Xu, Biling; Jiang, Hualiang; Chen, Kaixian; Luo, Cheng; Zhao, Yujun published the artcile< Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins>, SDS of cas: 118430-74-3, the main research area is benzodiazepine BET bromodomain BD2 protein inhibitor preparation cancer; BD2; BET protein; Bromodomain; Crystal structure; Selective.

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water mols., H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray anal. of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 118430-74-3 belongs to class pyrazoles-derivatives, and the molecular formula is C7H11N3, SDS of cas: 118430-74-3.

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

Huang, He; Strater, Zack M.; Rauch, Michael; Shee, James; Sisto, Thomas J.; Nuckolls, Colin; Lambert, Tristan H. published the artcile< Electrophotocatalysis with a trisaminocyclopropenium radical dication>, Computed Properties of 13788-92-6, the main research area is radical dication trisaminocyclopropenium photoelectrochem catalyst; C−H functionalization; Electrophotocatalysis; oxidation; radical dication; trisaminocyclopropenium ion.

Visible-light photocatalysis and electrocatalysis are two powerful strategies for the promotion of chem. reactions. Here, these two modalities are combined in an electrophotocatalytic oxidation platform. This chem. employs a trisaminocyclopropenium (TAC) ion catalyst, which is electrochem. oxidized to form a cyclopropenium radical dication intermediate. The radical dication undergoes photoexcitation with visible light to produce an excited-state species with oxidizing power (3.33 V vs. SCE) sufficient to oxidize benzene and halogenated benzenes via single-electron transfer (SET), resulting in C-H/N-H coupling with azoles. A rationale for the strongly oxidizing behavior of the photoexcited species is provided, while the stability of the catalyst is rationalized by a particular conformation of the cis-2,6-dimethylpiperidine moieties.

Angewandte Chemie, International Edition published new progress about C-H bond activation. 13788-92-6 belongs to class pyrazoles-derivatives, and the molecular formula is C9H7BrN2, Computed Properties of 13788-92-6.

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

Tan, Yun-Xuan; Liu, Xing-Yu; Zhang, Shuo-Qing; Xie, Pei-Pei; Wang, Xin; Feng, Kai-Rui; Yang, Shao-Qian; He, Zhi-Tao; Hong, Xin; Tian, Ping; Lin, Guo-Qiang published the artcile< An unconventional trans-exo-selective cyclization of alkyne-tethered cyclohexadienones initiated by rhodium(III)-catalyzed C-H activation via insertion relay>, Computed Properties of 13788-92-6, the main research area is rhodium carbon hydrogen activation catalysis alkyne cyclohexadienone cyclization.

Different from the established trans-endo-selective cyclization of alkyne-tethered electrophiles that involve an E/Z isomerization process, herein, the authors present a novel strategy to allow trans-exo-selective arylative cyclization of 1,6-enynes. Through initiation of rhodium(III)-catalyzed C-H activation, a diverse range of N-heterocyclic directing groups, including pyridine, pyrazole, imidazo[1,2-a] pyridine, benzoxazole, benzothiazole, and purine, was feasible for the cascade transformation, exhibiting high efficiency (up to 92% yield), broad substrate scope, and excellent functional group compatibility. Moreover, the modification of natural products and pharmaceutical compounds was also demonstrated to showcase its synthetic utility. Based on d. functional theory (DFT) calculations, a key three-membered ring intermediate through the insertion relay, rather than the direct E/Z isomerization of alkenyl rhodium species, controlled the stereochem. outcome for this trans-exo-selective cyclization. The subsequent ring-opening protonation of the more favored rotamer led to exclusive trans-exo-selectivity.

CCS Chemistry published new progress about C-H bond activation. 13788-92-6 belongs to class pyrazoles-derivatives, and the molecular formula is C9H7BrN2, Computed Properties of 13788-92-6.

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

Poslusney, Michael S.; Melancon, Bruce J.; Gentry, Patrick R.; Sheffler, Douglas J.; Bridges, Thomas M.; Utley, Thomas J.; Daniels, J. Scott; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Wood, Michael R. published the artcile< Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: The continued optimization of an MLPCN probe molecule>, Related Products of 1046832-21-6, the main research area is spirocycle preparation SAR human rat muscarinic M1 receptor selectivity; pos allosteric modulator SAR spirocycle MLPCN probe mol.

This Letter describes the further optimization of an MLPCN probe mol. (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles, e.g. I, possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.

Bioorganic & Medicinal Chemistry Letters published new progress about Homo sapiens. 1046832-21-6 belongs to class pyrazoles-derivatives, and the molecular formula is C11H19BN2O2, Related Products of 1046832-21-6.

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

Liu, Haidong; Ge, Liang; Wang, Ding-Xing; Chen, Nan; Feng, Chao published the artcile< Photoredox-Coupled F-Nucleophilic Addition: Allylation of gem-Difluoroalkenes>, Safety of 1-(4-Bromophenyl)-1H-pyrazole, the main research area is homoallylic trifluoromethane preparation; gem difluoroalkene photoredox coupled fluoroallylation; allylic compounds; fluorine; photochemistry; radicals; reaction mechanisms.

A novel strategy for the expedient construction of CF3-embeded tertiary/quaternary carbon centers was developed by taking advantage of photoredox catalysis. Thanks to a key step of single-electron oxidation, electron-rich gem-difluoroalkenes, which otherwise are essentially reluctant towards F-nucleophilic addition, now readily participate in this fluoroallylation reaction. Furthermore, this strategy provides an elegant example for the generation, as well as functionalization, of α-CF3-substituted benzylic radical intermediates using cheap and readily available starting materials.

Angewandte Chemie, International Edition published new progress about Allylation (fluoro). 13788-92-6 belongs to class pyrazoles-derivatives, and the molecular formula is C9H7BrN2, Safety of 1-(4-Bromophenyl)-1H-pyrazole.

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

Olsen, Kathryn L.; Jensen, Matthew R.; MacKay, James A. published the artcile< A mild halogenation of pyrazoles using sodium halide salts and Oxone>, Name: 4-Bromo-3-phenyl-1H-pyrazole, the main research area is pyrazole halogenation sodium halide oxone green chem.

A mild, inexpensive, and operationally simple pyrazole halogenation method utilizing Oxone and sodium halide salts is reported. This work documents 17 examples of alkyl, aryl, allyl, and benzyl substituted 4-chloro and 4-bromopyrazoles, obtained in up to 93% yield. Reactions are performed in water under ambient conditions and generation of organic byproducts is avoided.

Tetrahedron Letters published new progress about Alkali metal halides, sodium halides Role: RGT (Reagent), RACT (Reactant or Reagent). 13808-65-6 belongs to class pyrazoles-derivatives, and the molecular formula is C9H7BrN2, Name: 4-Bromo-3-phenyl-1H-pyrazole.

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