Tag: 100-200

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

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

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

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

Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-α and IL-6 inhibitors was written by Bharate, Sandip B.;Mahajan, Tushar R.;Gole, Yogesh R.;Nambiar, Mahesh;Matan, T. T.;Kulkarni-Almeida, Asha;Balachandran, Sarala;Junjappa, H.;Balakrishnan, Arun;Vishwakarma, Ram A.. And the article was included in Bioorganic & Medicinal Chemistry in 2008.Product Details of 3528-58-3 This article mentions the following:

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogs using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl–glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-α and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 (I) exhibited promising activity against IL-6 with 60-65% inhibition at 10 μM concentration Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC₅₀‘s of 0.2, 0.3 and 0.16 μM, resp. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 μM. In the experiment, the researchers used many compounds, for example, 1-Ethyl-1H-pyrazol-5-amine (cas: 3528-58-3Product Details of 3528-58-3).

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. 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.Product Details of 3528-58-3

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

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876 was written by Siebeneicher, Holger;Cleve, Arwed;Rehwinkel, Hartmut;Neuhaus, Roland;Heisler, Iring;Mueller, Thomas;Bauser, Marcus;Buchmann, Bernd. And the article was included in ChemMedChem in 2016.SDS of cas: 5334-39-4 This article mentions the following:

Despite the long-known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1-selective small-mol. inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high-throughput screen against a library of ∼3 million compounds was performed to find a small mol. with this challenging potency and selectivity profile. The N-(1H-pyrazol-4-yl)quinoline-4-carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure-activity relationship explorations, single-digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY-876 [N⁴-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo. In the experiment, the researchers used many compounds, for example, 3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4SDS of cas: 5334-39-4).

3-Methyl-4-nitro-1H-pyrazole (cas: 5334-39-4) 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.SDS of cas: 5334-39-4

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

Identification of ring-fused pyrazolo pyridin-2-ones as novel poly(ADP-ribose)polymerase-1 inhibitors was written by Moree, Wilna J.;Goldman, Phyllis;Demaggio, Anthony J.;Christenson, Erik;Herendeen, Dan;Eksterowicz, John;Kesicki, Edward A.;McElligott, David L.;Beaton, Graham. And the article was included in Bioorganic & Medicinal Chemistry Letters in 2008.Name: 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine This article mentions the following:

A novel class of PARP-1 inhibitors was identified containing a non-aromatic heterocycle or carbocycle fused to a pyrazolo pyridin-2-one. Compounds displayed low nanomolar binding activity in the PARP-1 binding assay and submicromolar activity in a cell based chemosensitization assay. In the experiment, the researchers used many compounds, for example, 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2Name: 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. An alternative way to synthesize multisubstituted pyrazoles is the Csingle bondH arylation of simple pyrazoles. 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.Name: 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine

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

Platinum(II) and palladium(II) complexes with 3,5-dimethyl-1-pyrazolylcarbamide was written by Safronova, L. A.;Shebaldova, A. D.. And the article was included in Koordinatsionnaya Khimiya in 1989.Recommanded Product: 3,5-Dimethyl-1H-pyrazole-1-carboxamide This article mentions the following:

MLCl₂ (M = Pd, Pt; L = 3,5-dimethyl-1-pyrazolylcarbamide) were prepared and characterized by IR and ¹H NMR spectra and colorimetry with SnCl₂. L coordinates through the pyridine N atom and the amino N atom. In the experiment, the researchers used many compounds, for example, 3,5-Dimethyl-1H-pyrazole-1-carboxamide (cas: 934-48-5Recommanded Product: 3,5-Dimethyl-1H-pyrazole-1-carboxamide).

3,5-Dimethyl-1H-pyrazole-1-carboxamide (cas: 934-48-5) belongs to pyrazole derivatives. Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. 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.Recommanded Product: 3,5-Dimethyl-1H-pyrazole-1-carboxamide

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

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor was written by Zhao, Yujun;Zhou, Bing;Bai, Longchuan;Liu, Liu;Yang, Chao-Yie;Meagher, Jennifer L.;Stuckey, Jeanne A.;McEachern, Donna;Przybranowski, Sally;Wang, Mi;Ran, Xu;Aguilar, Angelo;Hu, Yang;Kampf, Jeff W.;Li, Xiaoqin;Zhao, Ting;Li, Siwei;Wen, Bo;Sun, Duxin;Wang, Shaomeng. And the article was included in Journal of Medicinal Chemistry in 2018.Quality Control of 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine This article mentions the following:

We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5-b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K_i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-neg. breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclin. development. In the experiment, the researchers used many compounds, for example, 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine (cas: 141459-53-2Quality Control 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 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. 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.Quality Control of 1-(tert-Butyl)-3-methyl-1H-pyrazol-5-amine

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

Potent and Selective Ketoamide-Based Inhibitors of Cysteine Protease, Cathepsin K was written by Tavares, Francis X.;Deaton, David N.;Miller, Aaron B.;Miller, Larry R.;Wright, Lois L.;Zhou, Hui-Qiang. And the article was included in Journal of Medicinal Chemistry in 2004.Application In Synthesis of 1-Ethyl-1H-pyrazol-5-amine This article mentions the following:

Cathepsin K, a lysosomal cysteine protease of the papain superfamily, is abundantly and selectively expressed in osteoclasts, suggesting that this enzyme is crucial for bone resorption. Prevention of osteoclast-mediated bone resorption via inhibition of cathepsin K could be an effective approach to prevent osteoporosis. Potent and selective reversible ketoamide-based inhibitors have been identified in the present study. Using a known crystal structure of a ketoamide-based inhibitor, information from residues that form the P2/P3 pocket was used in the design of inhibitors that could allow for gains in selectivity and potency. Further, incorporation of P’ selective heterocycles, along with the P2/P3 modifications, is also described. These modifications have resulted in potent and selective cathepsin K inhibitors that allow for improvements in their physiochem. properties and represent a viable lead series for the discovery of new therapies for the prevention and treatment of osteoporosis. In the experiment, the researchers used many compounds, for example, 1-Ethyl-1H-pyrazol-5-amine (cas: 3528-58-3Application In Synthesis of 1-Ethyl-1H-pyrazol-5-amine).

1-Ethyl-1H-pyrazol-5-amine (cas: 3528-58-3) belongs to pyrazole derivatives. Pyrazoles, a five-membered heterocycle containing two adjacent nitrogen atoms, are the core structures found in a number of molecules that possess a wide range of pharmaceutical and agricultural activities. 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.Application In Synthesis of 1-Ethyl-1H-pyrazol-5-amine

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