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- Volume 1, Issue 1, 2001
Mini Reviews in Medicinal Chemistry - Volume 1, Issue 1, 2001
Volume 1, Issue 1, 2001
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Molecular Moments for Computer-Aided Drug Discovery
More LessCertain of the fundamental concepts underlying the utilization of comparative molecular moment (CoMMA) descriptors as measures of three-dimensional molecular similarity are reviewed. The results of a principal component regression (PCR) analyses of the five data sets previously examined by partial least squares (PLS) calculations are provided. The results further substantiate the utility of the CoMMA descriptors in predicting chemical and biological activity.
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Modifying TNF alpha for Therapeutic Use A Perspective on the TNF Receptor System
Authors: Akihiro Hasegawa, Watrau Takasaki, Mark I. Greene and Ramachandran MuraliTNF alpha is an inflammatory mediator that is relevant to several autoimmune diseases. Macromolecular inhibitors of TNF alpha have proven therapeutically useful in some preliminary studies. We have developed small molecule TNF alpha antagonist based on the crystal structure of TNF receptor complex. The TNF alpha inhibitor is specific and mediates biological function similar to the inhibitory soluble TNF receptor. This review focuses on development of small molecule anti-TNF alpha mimetics by us and current status of other agents.
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Recent Advances in Bioreductive Drug Targeting
Authors: M. A. Naylor and P. ThomsonAdvances in the chemistry of bioreductive drug activation have led to the design of hypoxia-selective drug delivery systems. These prodrugs, comprising a bioreductive trigger, linker and effector were first explored with nitrobenzyl quaternary ammonium mustards. Alternative nitroheterocycles were subsequently developed, together with new avenues of prodrug activation in ADEPT and GDEPT. Major advances have also been made in utilising indolequinone reductive chemistry based upon an appreciation of the kinetics of oxygen-sensitive reductive elimination.
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DNA Tetraplex-Binding Drugs Structure-Selective Targeting is Critical for Antitumour Telomerase Inhibition
Authors: Philip J. Perry and Terence C. JenkinsFour-stranded tetraplex ("G-quadruplex") DNA represents a new paradigm for the design of DNA-interactive antitumour drugs, as the formed DNA-drug complexes have been suggested to interfere with critical telomerase function. The unique structural features presented by tetraplex over duplex DNA have stimulated the design of small ligand molecules able to selectively promote the formation and-or stabilisation of such higher-order DNA structures. Current developments in tetraplex-targeted telomerase inhibitors, and importantly their DNA structural selectivity, are explored.
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Small Molecule Inhibitors of Serine Threonine Protein Phosphatases
Authors: Adam McCluskey and Jennette A. SakoffSerine(slash)threonine protein phosphatases have long been ignored as potential therapeutic targets for two reasons, one the biochemical significance of these proteins has not been appreciated and two, many natural protein phosphatase inhibitors are potent toxins and are considered unsuitable for clinical use. This review outlines the biochemical role of this protein family in cancer, cystic fibrosis, immunosuppression and, cardiac and neurological disorders. Particular emphasis is also given to the synthesis of selective small molecule inhibitors and their clinical
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Nitric Oxide-Releasing Nonsteroidal Anti-inflammatory Drugs Novel Gastrointestinal-Sparing Drugs
Authors: Upul Bandarage and David R. JaneroNonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.
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Enterohepatic Recirculation A Powerful Incentive for Drug Discovery in the Inosine Monophosphate Dehydrogenase Field
More LessWith the exception of organ transplant immunosuppression, the treatment of various IMPDH-dependent hyperproliferative diseases by MPA has failed due to the drugs EHC-induced GIT adverse effects. To influence its therapeutic index, novel formulations such as gastro-resistant MPA-Na (ERL080) or MPA cholestyramine combinations have been developed. Structurally novel IMPDH inhibitors have been discovered based on high throughput screening (pyridazoles) and rational design (methoxyphenyloxazoles). The clinical data on methoxyphenyloxazole derivatives such as VX-497 that is not expected to undergo EHC, will bring improved understanding of the relationship between IMPDH blockade and GIT toxicity.
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A Comparison of Methods for Pharmacophore Generation with the Catalyst Software and their Use for 3D-QSAR Application to a Set of 4-Aminopyridine Thrombin Inhibitors
Authors: P. A. Greenidge and J. WeiserThe method of structure-based pharmacophores for use in 3D-QSAR as implemented by Gillner and Greenidge (6) is further examined. Conformational models are generated using both Catalyst (3) and Macromodel (7). K i estimates obtained with the pharmacophore models are compared with observed values for a set of 4-aminopyridine thrombin inhibitors (8).
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Recent Advances in the Development of Dopamine D3 Receptor Agonists and Antagonists
Authors: A. M. Crider and Mark A. ScheidelerAdvances in molecular cloning techniques have allowed the characterization of five subtypes (D1 -D5 ) of dopamine (DA) receptors. The limbic location of the D3 receptor has led to speculation about its possible role in schizophrenia and drug abuse. Since the D 3 receptor is localized in the limbic region rather than the striatum, antipsychotics with D 3 receptor selectivity could be devoid of extrapyramidal side effects commonly seen with D 2 receptor antagonists. Recent work in our laboratory revealed that the benz(e)indole cis-(±)-44b demonstrated high selectivity for the D 3 receptor. This compound exhibits a typical antipsychotic profile without the motor effects found in commonly used antipsychotic agents. This mini-review will give a brief introduction on D 3 receptors and a detailed description of selectively-acting D 3 agonists and antagonists which have recently appeared in the literature.
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Structure-Metabolism Relationships Steric Effects and the Enzymatic Hydrolysis of Carboxylic Esters
More LessAfter a brief review of a number of issues related to the enzymatic hydrolysis of carboxylic esters, such as interspecies variability, mechanism, stereospecificity, and activation energy, and after an overview of relevant aspects related to the quantitative modeling of steric effects, the results of a recently developed quantitative structure-metabolism relationship model are discussed. They were obtained for in vitro human blood enzymatic hydrolysis of noncongener esters by introduction of the inaccessible solid angle as a novel measure of steric hindrance.
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Structure-Function Relationships in Chloroquine and Related 4-Aminoquinoline Antimalarials
More LessRecent publications have provided strong evidence that activity and cellular uptake of 4-aminoquinoline antimalarials depends on vacuolar haemoglobin degradation and that haematin is the drug target. Studies on haematin-quinoline interactions have provided insight into the structural requirements for these interactions and indications are that 4-aminoquinolines may act by inhibiting haemozoin formation. Structural requirements for this activity have also been reported recently and have led to construction of an empirical structure-function relationship for 4-aminoquinolines.
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Volumes & issues
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Volume 25 (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)
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