Category: piperidines

Teng, Mingxing published the artcileDevelopment of CDK2 and CDK5 Dual Degrader TMX-2172, Quality Control of 73874-95-0, the main research area is ovarian cancer CDK2 CDK5 dual degrader antiproliferative CCNE1; CDK2; CDK5; cancer; cell cycle; drug design; protein degradation.

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP-binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX-2172(I), a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX-2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1.

Angewandte Chemie, International Edition published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Quality Control of 73874-95-0.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Yamada, Ken published the artcileDiscovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma, Application of 1-N-Boc-2-Ethylpiperidin-4-one, the main research area is CETP inhibition piperidine analog hypertriglyceridemic plasma activity; piperidine analog preparation hypertriglyceridemic plasma activity.

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead mol. with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound I (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclin. efficacy and safety profile, the compound was advanced into clin. trials.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 324769-07-5 belongs to class piperidines, name is 1-N-Boc-2-Ethylpiperidin-4-one, and the molecular formula is C12H21NO3, Application of 1-N-Boc-2-Ethylpiperidin-4-one.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Zhu, Shulei published the artcileDesign, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation, Related Products of piperidines, the main research area is cancer HSP90 inhibitor SN38 antitumor toxicity pharmacokinetic.

Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b(I) showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chem. and biol. evaluation.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Related Products of piperidines.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

LaMarche, Matthew J. published the artcileIdentification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate, the main research area is cancer SHP2 inhibitor drug design TNO155 clin trials.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chem. scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochem., pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155(I), (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clin. trials for cancer.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Guo, Cuiping published the artcileMinimalist linkers suitable for irreversible inhibitors in simultaneous proteome profiling, live-cell imaging and drug screening, Computed Properties of 73874-95-0, the main research area is proteome profiling cell imaging drug screening linker fluorescent probe.

Activity-based protein profiling (ABPP) and bioimaging have been powerful approaches for in situ drug screening and target identification. However, these approaches are still hindered by the preparation of high-quality probes. To address this challenge, we developed a series of novel minimalist linkers for irreversible inhibitors by incorporation of various bioorthogonal handles into an α,β-unsaturated amide, a common moiety of many irreversible inhibitors. The linker-containing probes have been demonstrated to be suitable for simultaneous protein labeling, live cell imaging and drug screening.

Chemical Communications (Cambridge, United Kingdom) published new progress about Affinity labeling. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Computed Properties of 73874-95-0.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Anderson, Fiona M. published the artcileSynthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumor agents, COA of Formula: C7H15Cl2N, the main research area is structure activity antitumor bispyrrolidine DNA crosslinking.

We are seeking to develop more effective bifunctional alkylating agents as antitumor agents. We previously synthesized conformationally restricted nitrogen mustards containing one piperidine ring, then bispiperidine derivatives were designed and prepared with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. A bispiperidine with the shortest bridge of two carbon atoms was the most reactive bifunctional alkylating agent. In order to extend this work and investigate the effects of a change in the size of the heterocyclic systems, new bispyrrolidine salts 17-23 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-8 carbon atoms were synthesized from L-proline so that only the LL-enantiomers were produced. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. All of the bispyrrolidines were efficient cross-linkers of naked DNA apart from those with three-carbon (18) and four-carbon (19) bridges, in contrast to the results with the bispiperidines. A piperazine derivative 24 with two potential alkylating sites was also shown to be an efficient cross-linker, as was an alicyclic compound 25 with six carbon atoms between the two alkylating sites. Compounds 26 and 30 with an extra carbon atom between the nitrogen and the leaving group were not cross-linkers, as expected if aziridinium ion formation is crucial for crosslinking ability. The preformed aziridine 27 with a further alkylating site was an efficient cross-linker. Compounds 28-29 with only one potential alkylating center were not cross-linkers of DNA. None of the compounds, however, produced significant cytotoxicity in human tumor cells in vitro.

Anti-Cancer Drug Design published new progress about Alkylating agents. 27483-92-7 belongs to class piperidines, name is 2-(Chloromethyl)-1-methylpiperidine hydrochloride, and the molecular formula is C7H15Cl2N, COA of Formula: C7H15Cl2N.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Zang, Yingda published the artcileClaulansine F-donepezil hybrids as anti-Alzheimer’s disease agents with cholinergic, free-radical scavenging, and neuroprotective activities, Product Details of C10H20N2O2, the main research area is Claulansine donepezil hybrid preparation docking anticholinesterase Alzheimer neuroprotective; AChE inhibitory activity; Alzheimer’s disease; Claulansine F–donepezil hybrids; free-radical scavenging activity; neuroprotective effects.

The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. Twenty-six Claulansine F-donepezil hybrids I (X = nothing, CH2, CH2CH2; R1 = OMe, t-Bu; R2 = PhCH2, 2-FC6H4CH2, 4-ClC6H4CH2, etc.) were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63-4.62μM). Moreover, the compound I [X = CH2; R1 = t-Bu; R2 = 2-ClC6H4CH2; (II)] exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, the compound II could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, the compound II had stronger free-radical scavenging activity. Mol. docking studies revealed that II could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate the compound II as a leading structure worthy of further investigation.

Molecules published new progress about Alzheimer disease. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Product Details of C10H20N2O2.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Rabal, Obdulia published the artcileDiscovery of in Vivo Chemical Probes for Treating Alzheimer’s Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate, the main research area is sildenafil vardenafil orthoaminoanilide synthesis antiAlzheimer SAR PDE5 histone deacetylase; Alzheimer’s disease; PDE5 inhibition; chemical probes; class I HDAC selective inhibition; dual inhibitors; in vivo test.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer’s disease (AD), we have designed, synthesized, and tested novel chem. probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these mols. exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chem. series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biol. responses. The lead identification process led to compound I, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chem. probe; thus, I has been assayed in a mouse model of AD (Tg2576).

ACS Chemical Neuroscience published new progress about Alzheimer disease. 73874-95-0 belongs to class piperidines, name is tert-Butyl piperidin-4-ylcarbamate, and the molecular formula is C10H20N2O2, Recommanded Product: tert-Butyl piperidin-4-ylcarbamate.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Takai, Haruki published the artcileSynthesis of piperidine derivatives with a quinazoline ring system as potential antihypertensive agents, COA of Formula: C12H20Cl2N2, the main research area is quinazolinepiperidine derivative preparation antihypertensive; piperidine quinazoline derivative preparation antihypertensive.

A series of piperidine derivatives with a 2-oxo-1,2,3,4-tetrahydro-quinazoline or 2,4-dioxo-1,2,3,4-tetrahydroquinazoline ring at the 4-position were prepared and tested for antihypertensive activity in rats. Among the compds tested, I  [92311-03-0] and II  [92311-10-9] produced relatively strong hypotension in the spontaneously hypertensive rat model.

Chemical & Pharmaceutical Bulletin published new progress about Antihypertensives. 1205-72-7 belongs to class piperidines, name is 1-Benzylpiperidin-4-amine dihydrochloride, and the molecular formula is C12H20Cl2N2, COA of Formula: C12H20Cl2N2.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Takai, Haruki published the artcileSynthesis of 1- and 3-(1-substituted 4-piperidinyl)-1,2,3,4-tetrahydro-2-oxoquinazolines as potential antihypertensive agents, Application In Synthesis of 1205-72-7, the main research area is quinazolinylpiperidine antihypertensive adrenergic blocking preparation; piperidine quinazolinyl oxophenylethyl hydroxyphenethyl.

Piperidinylquinazolines, e.g. I [R = R1 = H, Cl, OMe; R = H, R1 = Cl, OMe; Z = O, (H, OH)] were prepared and tested for antihypertensive activity. I [Z = (H, OH)] were generally the most effective in lowering blood pressure in the spontaneous hypertensive rat model, and KF5908 [I, R = H, R1 = Cl, Z = (H, OH)] showed strong α-adrenergic blocking activity.

Chemical & Pharmaceutical Bulletin published new progress about Antihypertensives. 1205-72-7 belongs to class piperidines, name is 1-Benzylpiperidin-4-amine dihydrochloride, and the molecular formula is C12H20Cl2N2, Application In Synthesis of 1205-72-7.

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem