A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives

McGrath, Nicholas A.; Brichacek, Matthew; Njardarson, Jón T.

doi:10.1021/ed1003806

Cited by 943 publications

(740 citation statements)

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“…Although the most obvious GPCR modulators constitute some 26% of the top sellers and netted some $23.5 billion (9% of the global market share) of drug sales in the year 2000, these ϳ150 marketed drugs surprisingly target only ϳ20 of the ϳ750 known GPCR subtypes (Vassilatis et al, 2003;Overington et al, 2006). Moreover, as of 2008, 5 of the top 15 generic drugs and 7 (Milligan, 2009) of the top 15 prescription drugs targeted GPCRs (McGrath et al, 2010). Of those, only the leukotriene drugs are "new" GPCR targets.…”

Section: A Overview Of the Current G Protein-coupled Receptor Drug Dmentioning

confidence: 99%

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

2011

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Section: A Overview Of the Current G Protein-coupled Receptor Drug Dmentioning

confidence: 99%

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

2011

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“…Treatment of the reaction products with hydrogen peroxide yields the corresponding syn-configured afluoro b-hydroxy carboxylic acids which have > 98 %ee. The overall chemoenzymatic approach,i nw hich fluoropyruvate serves as af luoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.Fluorination can profoundly affect the conformation, bioavailability,m etabolism, pharmacokinetics and pharmacodynamics of bioactive small molecules.[1] Thei ntroduction of fluorine is therefore widely used to tune biological function, and around 20 %ofleading drugs contain at least one fluorine atom [2] (10 of the top 50 drugs in 2013 by US prescription [3] ). Examples of leading fluorinated pharmaceuticals include the cholesterol-lowering drug Rosuvastatin [4] and the antidiabetic drug Sitagliptin.…”

mentioning

confidence: 99%

“…[1] Thei ntroduction of fluorine is therefore widely used to tune biological function, and around 20 %ofleading drugs contain at least one fluorine atom [2] (10 of the top 50 drugs in 2013 by US prescription [3] ). Examples of leading fluorinated pharmaceuticals include the cholesterol-lowering drug Rosuvastatin [4] and the antidiabetic drug Sitagliptin.…”

mentioning

confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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The trans-o-hydroxybenzylidene pyruvate aldolasecatalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn-configured afluoro b-hydroxy carboxylic acids which have > 98 %ee. The overall chemoenzymatic approach,i nw hich fluoropyruvate serves as af luoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.Fluorination can profoundly affect the conformation, bioavailability,m etabolism, pharmacokinetics and pharmacodynamics of bioactive small molecules.[1] Thei ntroduction of fluorine is therefore widely used to tune biological function, and around 20 %ofleading drugs contain at least one fluorine atom [2] (10 of the top 50 drugs in 2013 by US prescription [3] ). Examples of leading fluorinated pharmaceuticals include the cholesterol-lowering drug Rosuvastatin [4] and the antidiabetic drug Sitagliptin. [4] Thec ontrolled formation of fluorine-substituted stereocentres,h owever, presents as ignificant challenge.M ost usually,t he challenge is addressed by stereoselective CÀF bond formation. Fore xample,t he fluorination of allylic silanes is often diastereoselective, [5] and organo- [6] and Pd- [7] catalysed methods enable the enantioselective a-fluorination of carbonyl compounds. Stereoselective CÀCbond formation could provide acomplementary approach for controlling fluorine-bearing stereocentres (Scheme 1). However,aldol (and related) reactions of esters of fluoroacetic acid generally exhibit poor diastereoselectivity (e.g.r eactions of lithium enolates, [8] Reformatsky reactions [9] and Mukayama aldol reactions [10]

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“…Proteinaceous drugs have gained importance as reflected by their impressive advent among the top pharmaceutical products [27]. The size of therapeutically used protein formats can vary significantly.…”

Section: Proteins As Site-specific Drugsmentioning

confidence: 99%

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

et al. 2014

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Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular "personalized medicine", depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

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A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives

Cited by 943 publications

References 1 publication

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

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