Search results for "piperidine"

Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site.

2008

Drugs used to treat various disorders target GABA A receptors. To develop alpha subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [(3)H]muscimol binding and in patch-clamp experiments with heterologously expressed GABA A alpha ibeta 3gamma 2 receptors (i = 1-6). The effects of 5-aminomethyl-3 H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all alpha subunit isoforms. 5-pipe…

Identifying three-way DNA junction-specific small-molecules

2012

Three-way junction DNA (TWJ-DNA, also known as 3WJ-DNA) is an alternative secondary DNA structure comprised of three duplex-DNAs that converge towards a single point, termed the branch point. This point is characterized by unique geometrical properties that make its specific targeting by synthetic small-molecules possible. Such a targeting has already been demonstrated in the solid state but not thoroughly biophysically investigated in solution. Herein, a set of simple biophysical assays has been developed to identify TWJ-specific small-molecule ligands; these assays, inspired by the considerable body of work that has been reported to characterize the interactions between small-molecules an…

Atom-based Stochastic and non-Stochastic 3D-Chiral Bilinear Indices and their Applications to Central Chirality Codification

2006

Abstract Non-stochastic and stochastic 2D bilinear indices have been generalized to codify chemical structure information for chiral drugs, making use of a trigonometric 3D-chirality correction factor. In order to evaluate the effectiveness of this novel approach in drug design we have modeled the angiotensin-converting enzyme inhibitory activity of perindoprilate's σ-stereoisomers combinatorial library. Two linear discriminant analysis models, using non-stochastic and stochastic linear indices, were obtained. The models had shown an accuracy of 95.65% for the training set and 100% for the external prediction set. Next the prediction of the σ-receptor antagonists of chiral 3-(3-hydroxypheny…

Pharmacology and safety of tofacitinib in ulcerative colitis.

2020

The use of Janus kinase (JAK) inhibitors is a new approach in the therapy of inflammatory diseases with immune base. Tofacitinib is one of these inhibitors targeting JAK1 and JAK3, and its efficacy has been demonstrated in the treatment of moderate to severe ulcerative colitis (UC). It is a small synthetic molecule administered orally, with a fast bioavailability and elimination rate, predictable pharmacokinetics and lack of immunogenicity, which are convenient characteristics for both efficacy and safety. This article reviews the pharmacological characteristics of tofacitinib and its safety profile.

Stereoselective solid-phase synthesis of chiral piperidine derivatives by using an immobilized galactose auxiliary.

2003

2019

Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successfu…

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mant…

2017

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the R…

Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial.

2021

Abstract Background The single‐arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment. Methods Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer‐related genes was examined. Responder‐ versus nonresponder‐associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created …

Survival risk score for real-life relapsed/refractory chronic lymphocytic leukemia patients receiving ibrutinib. A campus CLL study

2020

Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study

2021

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