Month: November 2022

Civiello, Rita L. published the artcileSynthesis and SAR of calcitonin gene-related peptide (CGRP) antagonists containing substituted aryl-piperazines and piperidines, Synthetic Route of 180698-19-5, the publication is Bioorganic & Medicinal Chemistry Letters (2016), 26(4), 1229-1232, database is CAplus and MEDLINE.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide implicated in the pathophysiol. of migraine. In seeking CGRP antagonists with improved oral bioavailability, metabolic stability, and pharmacokinetic properties, lower mol. weight, structurally simpler piperidine and piperazine analogs of BMS-<694153≥ were prepared Several have nM binding affinity in vitro. The synthesis and SAR of these substituted piperidine and piperazine CGRP antagonists are discussed.

Bioorganic & Medicinal Chemistry Letters published new progress about 180698-19-5. 180698-19-5 belongs to piperazines, auxiliary class Piperazine,Benzene, name is 1-Biphenyl-4-yl-piperazine, and the molecular formula is C16H18N2, Synthetic Route of 180698-19-5.

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

Guarino, Carla published the artcileProlonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases, Application of 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, the publication is Biochemical Pharmacology (Amsterdam, Netherlands) (2017), 52-67, database is CAplus and MEDLINE.

Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of an N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine proteases activities and cause Papillon-Lefevre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome anal. of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. The authors aimed to exptl. inactivate and lower neutrophil elastase-like proteases by pharmacol. blocking of CatC-dependent maturation in cell-based assays and in vivo. Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. The authors confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. The authors also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclin. results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacol. inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans.

Biochemical Pharmacology (Amsterdam, Netherlands) published new progress about 914610-39-2. 914610-39-2 belongs to piperazines, auxiliary class Piperazine,Boronic acid and ester,Sulfamide,Benzene,Piperazine,Boronate Esters,Boronic acid and ester,, name is 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, and the molecular formula is C17H27BN2O4S, Application of 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine.

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

Boursalian, Gregory B. published the artcileCharge-transfer-directed radical substitution enables para-selective C-H functionalization, Product Details of C16H18N2, the publication is Nature Chemistry (2016), 8(8), 810-815, database is CAplus and MEDLINE.

Efficient C-H functionalization requires selectivity for specific C-H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C-H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theor. tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C-H functionalization reactions.

Nature Chemistry published new progress about 180698-19-5. 180698-19-5 belongs to piperazines, auxiliary class Piperazine,Benzene, name is 1-Biphenyl-4-yl-piperazine, and the molecular formula is C16H18N2, Product Details of C16H18N2.

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

Singh, Gagandip published the artcileModeling of LIM-kinase 2 inhibitory activity of pyrrolopyrimidine analogues: useful in treatment of ocular hypertension and glaucoma, Category: piperazines, the publication is Medicinal Chemistry (2013), 9(3), 402-409, database is CAplus and MEDLINE.

The LIM-Kinase 2 (LIMK2) inhibitory activity of a series of pyrrolopyrimidine analogs has been analyzed through combinatorial protocol in multiple linear regressions (CP-MLR) and partial least square (PLS) using different descriptors obtained from DRAGON software. The empirical, topol. and charge descriptors have led to statistically significant QSAR models and showed good external predictivity as reflected in test set R² values (0.782 to 0.888). The obtained structure-activity correlations underlined the significance of bulkiness and mol. polarizability in improving the activity. The topol. descriptors suggested that open chain or branched substituents are favorable while cyclic /ring substituents are unfavorable for the activity. The descriptors identified in the study showed that pyrrolopyrimidine scaffold holds scope for modulating LIMK2 inhibitory activity. The study gives a direction for further exploration of chem. space of pyrrolopyrimidine analogs as LIMK2 inhibitors.

Medicinal Chemistry published new progress about 1116571-01-7. 1116571-01-7 belongs to piperazines, auxiliary class Other Aromatic Heterocyclic,Piperazine,Chiral,Nitrile,Bromide,Carbamidine,Amine,Benzene, name is (S)-N-(3-Bromophenyl)-N’-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide, and the molecular formula is C8H7NaO4S, Category: piperazines.

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

Ehrlich, Katharina published the artcileDopamine D₂, D₃, and D₄ Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding, Recommanded Product: 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, the publication is Journal of Medicinal Chemistry (2009), 52(15), 4923-4935, database is CAplus and MEDLINE.

Assembling phenylpiperazines with 7a-azaindole via different spacer elements, we developed subtype selective dopamine receptor ligands, e.g. I, preferentially interacting with D₄, D₂, and D₃, resp. To complete this set, the methylthio analogs exceeding the affinity of methoxy derivatives by one order of magnitude and a structural intermediate II were synthesized. These chem. similar but biol. divergent target compounds served as mol. probes for radioligand displacement experiments, mutagenesis, and docking studies on homol. models based on the recent crystal structure of the β₂-adrenergic receptor. Specific interactions with the highly conserved amino acids Asp^3.32 and His^6.55 and less conserved residues at positions 2.61, 2.64, 3.28, and 3.29 were identified. Inclusion of a carefully modeled extracellular loop 2 displayed two nonconserved residues in EL2 that differently contribute to ligand binding. Obviously, subtype selectivity is caused by nonconserved but frequently mediated by conserved amino acids.

Journal of Medicinal Chemistry published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Recommanded Product: 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine.

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

Brebion, Franck published the artcileDiscovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis, HPLC of Formula: 180698-19-5, the publication is Journal of Medicinal Chemistry (2021), 64(6), 2937-2952, database is CAplus and MEDLINE.

There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochem. activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC₅₀ < 1.5μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clin. study in patients with knee OA (NCT03595618).

Journal of Medicinal Chemistry published new progress about 180698-19-5. 180698-19-5 belongs to piperazines, auxiliary class Piperazine,Benzene, name is 1-Biphenyl-4-yl-piperazine, and the molecular formula is C16H18N2, HPLC of Formula: 180698-19-5.

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

Keith, John M. published the artcileDual serotonin transporter/histamine H₃ ligands: Optimization of the H₃ pharmacophore, Application In Synthesis of 71260-16-7, the publication is Bioorganic & Medicinal Chemistry Letters (2007), 17(3), 702-706, database is CAplus and MEDLINE.

A series of tetrahydroisoquinolines, e.g., I, acting as dual histamine H₃/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH₃ was developed. In vitro and in vivo data are discussed.

Bioorganic & Medicinal Chemistry Letters published new progress about 71260-16-7. 71260-16-7 belongs to piperazines, auxiliary class Piperazine, name is 2-Methyl-1-(piperazin-1-yl)propan-1-one, and the molecular formula is C8H16N2O, Application In Synthesis of 71260-16-7.

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

Kortagere, Sandhya published the artcileCertain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain, Category: piperazines, the publication is Molecular Pharmacology (2004), 66(6), 1491-1499, database is CAplus and MEDLINE.

We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-{[4-(4-iodophenyl)piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methylspiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]2-(1H)-quinolinone] (Schetz et al., 2000). Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and mol. models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20-96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2-selective methylspiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.

Molecular Pharmacology published new progress about 337972-47-1. 337972-47-1 belongs to piperazines, auxiliary class Inhibitor, name is 2-((4-(4-Chlorophenyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine, and the molecular formula is C18H19ClN4, Category: piperazines.

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

Wilson, Colin R. published the artcileNovel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure-Activity Relationship and Target Identification Studies, Recommanded Product: 6-(4-Methylpiperazin-1-yl)pyridin-3-amine, the publication is Journal of Medicinal Chemistry (2017), 60(24), 10118-10134, database is CAplus and MEDLINE.

A BioFocus DPI SoftFocus library of ∼35,000 compounds was screened against Mycobacterium tuberculosis (Mtb) to identify novel hits with antitubercular activity. The hits were evaluated in biol. triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc₁ complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clin. Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed This suggested a novel mechanism of action, which was confirmed by chemoproteomic anal. leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochem. properties.

Journal of Medicinal Chemistry published new progress about 55403-35-5. 55403-35-5 belongs to piperazines, auxiliary class Pyridine,Piperazine,Amine, name is 6-(4-Methylpiperazin-1-yl)pyridin-3-amine, and the molecular formula is C10H4BrF10N, Recommanded Product: 6-(4-Methylpiperazin-1-yl)pyridin-3-amine.

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

Butini, Stefania published the artcileDiscovery of a New Class of Potential Multifunctional Atypical Antipsychotic Agents Targeting Dopamine D₃ and Serotonin 5-HT_1A and 5-HT_2A Receptors: Design, Synthesis, and Effects on Behavior, Safety of 1-(3-Cyanophenyl)piperazine, the publication is Journal of Medicinal Chemistry (2009), 52(1), 151-169, database is CAplus and MEDLINE.

Dopamine D₃ antagonism combined with serotonin 5-HT_1A and 5-HT_2A receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacol. features of 5i are a high affinity for dopamine D₃, serotonin 5-HT_1A and 5-HT_2A receptors, together with a low affinity for dopamine D₂ receptors (to minimize extrapyramidal side effects), serotonin 5-HT_2C receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacol. and biochem. data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

Journal of Medicinal Chemistry published new progress about 178928-58-0. 178928-58-0 belongs to piperazines, auxiliary class Piperazine,Nitrile,Benzene, name is 1-(3-Cyanophenyl)piperazine, and the molecular formula is C11H13N3, Safety of 1-(3-Cyanophenyl)piperazine.

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