Month: February 2023

Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656 was written by Waring, Michael J.;Clarke, David S.;Fenwick, Mark D.;Godfrey, Linda;Groombridge, Sam D.;Johnstone, Craig;McKerrecher, Darren;Pike, Kurt G.;Rayner, John W.;Robb, Graeme R.;Wilson, Ingrid. And the article was included in MedChemComm in 2012.Safety of 1-Ethyl-1H-pyrazol-3-amine This article mentions the following:

Glucokinase plays a central role in glucose homeostasis and small mol. activators of the glucokinase enzyme have been the subject of significant pharmaceutical research in the quest for agents capable of delivering improved glycemic control. Here we describe our medicinal chem. campaign to improve on our previously described development candidate in this area, AZD1092, focussed on removal of Ames liability and improved permeability characteristics. This work culminated in the superior compound AZD1656 which has progressed to phase 2 clin. trials. In the experiment, the researchers used many compounds, for example, 1-Ethyl-1H-pyrazol-3-amine (cas: 55361-49-4Safety of 1-Ethyl-1H-pyrazol-3-amine).

1-Ethyl-1H-pyrazol-3-amine (cas: 55361-49-4) belongs to pyrazole derivatives. The 1H-pyrazole provides an excellent means by which to provide the requisite hydrogen bond acceptor–donor motifs, whether as a monocyclic ring or as a fused indazole ring. Pyrazoles and pyrimidines have diverse biological and pharmacological activities. There are a number of antimicrobial compounds containing pyrazole moiety as the core unit. Pyrazofurin is important antimicrobial drug and 2-methylpyrimidine-4-ylamine derivatives I and II were found to be effective inhibitors of Escherichia coli PDHc-E1 with antibacterial and antifungal activity.Safety of 1-Ethyl-1H-pyrazol-3-amine

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

Discovery and Preclinical Characterization of 1-Methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]-pyrazine (PF470): A Highly Potent, Selective, and Efficacious Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator was written by Zhang, Lei;Balan, Gayatri;Barreiro, Gabriela;Boscoe, Brian P.;Chenard, Lois K.;Cianfrogna, Julie;Claffey, Michelle M.;Chen, Laigao;Coffman, Karen J.;Drozda, Susan E.;Dunetz, Joshua R.;Fonseca, Kari R.;Galatsis, Paul;Grimwood, Sarah;Lazzaro, John T.;Mancuso, Jessica Y.;Miller, Emily L.;Reese, Matthew R.;Rogers, Bruce N.;Sakurada, Isao;Skaddan, Marc;Smith, Deborah L.;Stepan, Antonia F.;Trapa, Patrick;Tuttle, Jamison B.;Verhoest, Patrick R.;Walker, Daniel P.;Wright, Ann S.;Zaleska, Margaret M.;Zasadny, Kenneth;Shaffer, Christopher L.. And the article was included in Journal of Medicinal Chemistry in 2014.Electric Literature of C7H6ClN3 This article mentions the following:

A novel series of pyrazolopyrazines is herein disclosed as mGluR5 neg. allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacol. potency with physicochem. and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]-pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicol. study. In the experiment, the researchers used many compounds, for example, 6-Chloro-1-methylpyrazolo[5,4-b]pyridine (cas: 63725-52-0Electric Literature of C7H6ClN3).

6-Chloro-1-methylpyrazolo[5,4-b]pyridine (cas: 63725-52-0) belongs to pyrazole derivatives. As is the case with imidazoles, the pyrazole ring offers many opportunities to create new multiring systems that incorporate this heterocycle. Pyrazole rings have been used as core components of several leading non-steroidal anti-inflammatory drugs (NSAIDs) and antihypertensive drugs. It has also been found to be useful as a bifunctional ligand for metal catalysis.Electric Literature of C7H6ClN3

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

Synthesis of pyrazolo[3′,4′:4,5]pyrimido [2,3-c][1,4] benzoxazines. A new heterocyclic ring system was written by Reddy, P. S. N.;Reddy, Pragati;Reddy, G. Jagath;Rao, K. Srinivasa. And the article was included in Heterocyclic Communications in 2003.SDS of cas: 14678-93-4 This article mentions the following:

A series of 4-oxo-pyrazolo[3′,4′:4,5]pyrimido[2,3-c][1,4] benzoxazines I (R¹ = H, Cl, F, Me, COMe; R² = H, Cl, Me; R³ = H, Me) were prepared by cyclocondensation of 1,4-benzoxazinones with 5-aminopyrazole-4-carboxylic acids in a single step. In the experiment, the researchers used many compounds, for example, 5-Amino-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid (cas: 14678-93-4SDS of cas: 14678-93-4).

5-Amino-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid (cas: 14678-93-4) belongs to pyrazole derivatives. Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. Pyrazoles are commonly used scaffold molecules in drug discovery projects. The use of pyrazole derivatives is based on their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, neuroleptic, anticonvulsant, monoamine oxidase inhibitory, antidiabetic and antibacterial activities.SDS of cas: 14678-93-4

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

NMR studies in heterocyclic series. XIV. Phenomena of restricted rotation observed in N COR derivatives of azoles and 2-pyrazolines was written by Elguero, Jose;Marzin, Claude;Pappalardo, Louis. And the article was included in Bulletin de la Societe Chimique de France in 1974.SDS of cas: 934-48-5 This article mentions the following:

NMR data were obtained for all the 1-acetyl-monosubstituted 5-membered N heterocycles (pyrrole through tetrazole), for pyrazoles I (R, R1, R2, and X given: MeO, H, H, O; MeO, Me, Me, O; NH2, H, H, O; NH2, Me, Me, O; NH2, Me, Me, NH; NH2, Me, Me, NH2+), and for 2-pyrazolines II (R = Me, MeO, NH2, NMe2; R1 = R3 = Me, R2 = H; R = MeO, NMe2, R1 = Me2CH, R2 = Me, R3 = H). Rotational barriers were calculated for I (R = MeO, R1 = R2 = H, X = O; R = NH2, R1 = R2 = H, Me, X = O) and for II (R = MeO, R1 = Me2CH, R2 = Me, R3 = H; R = NH2, R1 = R3 = Me, R2 = H). Solvent effects on NMR were shown and the inability to calculate rotational barriers for the 1-acetyl compounds and the hindered rotation of the 1-carbamoyl compounds were discussed. In the experiment, the researchers used many compounds, for example, 3,5-Dimethyl-1H-pyrazole-1-carboxamide (cas: 934-48-5SDS of cas: 934-48-5).

3,5-Dimethyl-1H-pyrazole-1-carboxamide (cas: 934-48-5) belongs to pyrazole derivatives. As is the case with imidazoles, the pyrazole ring offers many opportunities to create new multiring systems that incorporate this heterocycle. The presence of both electronegative nitrogen atoms in the pyrazole ring reduces the electron density of the C3- and C5-positions leaving electron density of C4-position unaltered. Thus the C4-position is vulnerable to electrophilic attack. The C3 electrophilic-position may undergo deprotonation in the presence of a strong base leading to ring opening.SDS of cas: 934-48-5

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

Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors was written by Barlaam, Bernard;Boiko, Scott;Boyd, Scott;Dry, Hannah;Gingipalli, Lakshmaiah;Ikeda, Timothy;Johnson, Tony;Kawatkar, Sameer;Lorthioir, Olivier;Pike, Andy;Pollard, Hannah;Read, Jon;Su, Qibin;Wang, Haiyun;Wang, Huimin;Wang, Lianghe;Wang, Peng;Edmondson, Scott D.. And the article was included in Bioorganic & Medicinal Chemistry Letters in 2020.Quality Control of 3-Methyl-4-nitro-1H-pyrazole This article mentions the following:

Hybridization of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimization of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallog. Further optimization of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition. In the experiment, the researchers used many compounds, for example, 3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4Quality Control of 3-Methyl-4-nitro-1H-pyrazole).

3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4) belongs to pyrazole derivatives. Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. Pyrazoles can be selectively lithiated at different carbons and subsequently react with electrophiles depending on the substitution patterns.Quality Control of 3-Methyl-4-nitro-1H-pyrazole

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

New functionalized C,C-pyridylpyrazoles: synthesis and cation binding properties was written by Radi, Smaail;Attayibat, Ahmed;Ramdani, Abdelkrim;Bacquet, Maryse. And the article was included in Journal of Chemical Research in 2009.Application of 19959-77-4 This article mentions the following:

The synthesis of two new C,C-pyridylpyrazole isomers with a functionalized arm is described. The complexation capabilities of these ligands compared to their homologues towards bivalent metals (Hg²⁺, Cd²⁺, Pb²⁺, Cu²⁺, Zn²⁺) and alkali metal ions (K⁺, Na⁺, Li⁺) were investigated using a liquid-liquid extraction process. The percentage limits of extraction were determined by at. absorption measurements. In the experiment, the researchers used many compounds, for example, 2-(5-Methyl-1H-pyrazol-3-yl)pyridine (cas: 19959-77-4Application of 19959-77-4).

2-(5-Methyl-1H-pyrazol-3-yl)pyridine (cas: 19959-77-4) belongs to pyrazole derivatives. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugated acid 2.49 at 25 °C).Pyrazole used as a ligand to prepare organometallic compounds. Pyrazoles are commonly used scaffold molecules in drug discovery projects. The use of pyrazole derivatives is based on their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, neuroleptic, anticonvulsant, monoamine oxidase inhibitory, antidiabetic and antibacterial activities.Application of 19959-77-4

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

Use of Modeling and Process Analytical Technologies in the Design of a Catalytic Amination Reaction: Understanding Oxygen Sensitivity at the Lab and Manufacturing Scales was written by Merritt, Jeremy M.;Buser, Jonas Y.;Campbell, Alison N.;Fennell, Jared W.;Kallman, Neil J.;Koenig, Thomas M.;Moursy, Hossam;Pietz, Mark A.;Scully, Norma;Singh, Utpal K.. And the article was included in Organic Process Research & Development in 2014.Application In Synthesis of 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine This article mentions the following:

A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process anal. technol. alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and addnl. degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines. In the experiment, the researchers used many compounds, for example, 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2Application In Synthesis of 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine).

1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2) belongs to pyrazole derivatives. The strategies for the synthesis of pyrazoles generally can be applied for the construction of indazoles. Pyrazole the presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Application In Synthesis of 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine

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

Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators was written by Wieting, Joshua M.;Vadukoot, Anish K.;Sharma, Swagat;Abney, Kristopher K.;Bridges, Thomas M.;Daniels, J. Scott;Morrison, Ryan D.;Wickman, Kevin;Weaver, C. David;Hopkins, Corey R.. And the article was included in ACS Chemical Neuroscience in 2017.SDS of cas: 141459-53-2 This article mentions the following:

The G protein-gated inwardly-rectifying potassium channels (GIRK, K_ir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiol. processes and as potential targets for numerous indications. Previously reported urea containing mols. as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent K_p > 0.6). In the experiment, the researchers used many compounds, for example, 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2SDS of cas: 141459-53-2).

1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2) belongs to pyrazole derivatives. Pyrazole has two ring nitrogen atoms in which N1 is pyrrolic and N2 is pyridine-like. The N1 nitrogen is not reactive but is deprotonated in the presence of a base-forming anion. Pyrazoles are commonly used scaffold molecules in drug discovery projects. The use of pyrazole derivatives is based on their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, neuroleptic, anticonvulsant, monoamine oxidase inhibitory, antidiabetic and antibacterial activities.SDS of cas: 141459-53-2

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

Assessment of computational tools for predicting supramolecular synthons was written by Sandhu, Bhupinder;McLean, Ann;Sinha, Abhijeet S.;Desper, John;Aakeroy, Christer B.. And the article was included in Chemistry (Basel, Switzerland) in 2021.Quality Control of 3-(1H-Pyrazol-3-yl)pyridine This article mentions the following:

The ability to predict the most likely supramol. synthons in a crystalline solid is a valuable starting point for subsequently predicting the full crystal structure of a mol. with multiple competing mol. recognition sites. Energy and informatics-based prediction models based on mol. electrostatic potentials (MEPs), hydrogen-bond energies (HBE), hydrogen-bond propensity (HBP), and hydrogen-bond coordination (HBC) were applied to the crystal structures of twelve pyrazole-based mols. HBE, the most successful method, correctly predicted 100% of the exptl. observed primary intermol.-interactions, followed by HBP (87.5%), and HBC = MEPs (62.5%). A further HBC anal. suggested a risk of synthon crossover and synthon polymorphism in mols. with multiple binding sites. These easy-to-use models (based on just 2-D chem. structure) can offer a valuable risk assessment of potential formulation challenges. In the experiment, the researchers used many compounds, for example, 3-(1H-Pyrazol-3-yl)pyridine (cas: 45887-08-9Quality Control of 3-(1H-Pyrazol-3-yl)pyridine).

3-(1H-Pyrazol-3-yl)pyridine (cas: 45887-08-9) belongs to pyrazole derivatives. An alternative way to synthesize multisubstituted pyrazoles is the Csingle bondH arylation of simple pyrazoles. The pyrazole ring is resistant to oxidation and reduction but the groups, such as alkyl and formyl attached to the ring, are oxidized to respective acids. Only electrolytic oxidation, ozonolysis, and a strong base cause ring opening.Quality Control of 3-(1H-Pyrazol-3-yl)pyridine

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

Synthesis and Biological Evaluation of New Selective Cytotoxic Cyclolignans Derived from Podophyllotoxin was written by Castro, Maria Angeles;del Corral, Jose Maria Miguel;Gordaliza, Marina;Garcia, Pablo A.;Gomez-Zurita, Maria Antonia;Garcia-Gravalos, Maria Dolores;de la Iglesia-Vicente, Janis;Gajate, Consuelo;An, Feiyun;Mollinedo, Faustino;San Feliciano, Arturo. And the article was included in Journal of Medicinal Chemistry in 2004.Recommanded Product: 1-Ethyl-1H-pyrazol-5-amine This article mentions the following:

Podophyllotoxin and some of its derivatives are cyclolignans currently used for removing warts and in the clin. treatment of malign neoplasms. As such, they were an objective of the scientific community for decades, in the search for more potent and more selective anticancer agents. Interest in the chemoinduction of drug selectivity led to the design and preparation of new podophyllotoxin derivatives by reaction of podophyllic aldehyde with aliphatic, aromatic, and heteroaromatic amines. Several of the resulting imines displayed a significant selectivity against human colon carcinoma cells, even higher than that of the starting aldehyde. Addnl. biol. studies indicate that these derivatives induce microtubule depolymerization, arrest cells at the G₂/M phase of cell cycle, and are able to induce a delayed apoptosis after 48 h of treatment, characterized by caspase-3 activation. In the experiment, the researchers used many compounds, for example, 1-Ethyl-1H-pyrazol-5-amine (cas: 3528-58-3Recommanded Product: 1-Ethyl-1H-pyrazol-5-amine).

1-Ethyl-1H-pyrazol-5-amine (cas: 3528-58-3) belongs to pyrazole derivatives. Pyrazole has two ring nitrogen atoms in which N1 is pyrrolic and N2 is pyridine-like. The N1 nitrogen is not reactive but is deprotonated in the presence of a base-forming anion. Protonation of pyrazole in strong acid leads to pyrazolium cations, which undergo electrophilic substitution preferentially at C3 rather than C4. The pyrazole anion is not reactive toward nucleophiles but is mostly reactive to electrophiles.Recommanded Product: 1-Ethyl-1H-pyrazol-5-amine

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