1,721,046 research outputs found
Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective
Get PDFIntroduction: Ligand efficiency metrics are almost universally accepted as a valuable indicator of compound quality and an aid to reduce attrition. Areas covered: In this review, the authors describe ligand efficiency metrics giving a balanced overview on their merits and points of weakness in order to enable the readers to gain an informed opinion. Relevant theoretical breakthroughs and drug-like properties are also illustrated. Several recent exemplary case studies are discussed in order to illustrate the main fields of application of ligand efficiency metrics. Expert opinion: As a medicinal chemist guide, ligand efficiency metrics perform in a context- and chemotype-dependent manner; thus, they should not be used as a magic box. Since the â big bangâ of efficiency metrics occurred more or less ten years ago and the average time to develop a new drug is over the same period, the next few years will give a clearer outlook on the increased rate of success, if any, gained by means of these new intriguing tools
Label-free, Reagentless, Straightforward Capillary Electrophoretic Method to Individuate Potent Calmodulin Ligands
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Separation and quantitative determination of mexiletine and its metabolites by capillary zone electrophoresis
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
One-step synthesis of homochiral O-aryl and O-heteroaryl mandelic acids and their use as efficient 1H NMR chiral solvating agents
No full textJob and Buchwald's one-step copper-promoted arylation of hydroxyl groups was explored and modified so that it could be applied to the coupling of mandelic acid with several halobenzenes and haloheteroarenes. A number of new homochiral O-aryl and O-heteroaryl mandelic acids, generally presenting high enantiomeric purities, were obtained. Although yields were moderate at the best, ranging from 9% to 41%, the reaction was convenient enough to prepare new mandelic acid derivatives, some of which performed as efficient chiral solvating agents (CSAs) for the direct H-1 NMR ee value determination of several clinically and pharmacologically relevant amines
An improved synthesis of m-hydroxymexiletine, a potent mexiletine metabolite
No full textm-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels (hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid
The Crystal Structure of N-[(2E)-3-(4-Chlorophenyl)prop-2-en-1-yl]-4-methoxy-N-methylbenzenesulfonamide
No full textThe title compound C17H18ClNO3S crystallizes in the monoclinic P21/c space group with unit cell parameters a = 15.040 (3) Å, b = 9.151 (6) Å, c = 13.868 (7) Å, β = 116.38 (5)°. Chlorophenyl and methoxyphenyl ring planes are approximately perpendicular and the two moieties form an angle of 82.2°. The crystal packing is stabilized by π–π and Cl–π interactions, which occur between parallel methoxyphenyl and chlorophenyl moieties. Dipolar intermolecular contacts, mainly involving the oxygen atoms and C–H, also contribute to the crystal network. Graphical Abstract: The title compound is formed in the synthetic route for the production of potent inhibitors of calmodulin. Its crystal structure shows the chlorophenyl and methoxyphenyl moieties forming an angle of 82.2°. The crystal packing is stabilized by π–π, Cl–π and dipolar intermolecular contacts. [Figure not available: see fulltext.]
Recent trends in the discovery of small molecule blockers of sodium channels
No full textVoltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations. As a result, VGSC have never stopped attracting the attention of medicinal chemists and the quest for novel drugs to treat these ion channels-associated diseases continues. In this review, VGSC blocking agents reported in the last lustrum are scrutinised with the aim to give a medicinal chemistry perspective on the most interesting compounds classified on the basis of (i) potential therapeutic application, (ii) targeted VGSC isoforms, and (iii) chemical scaffolds. Finally, the clinical potential of selected drug candidates from each chemotype is evaluated by comparing their ligand efficiency metrics. Possible routes for improvement of these preclinical candidates are also discussed
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