- Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)
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High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.
- Breinbauer, Rolf,Doler, Carina,Fuchs, Elisabeth,Grabner, Gernot F.,Mayer, Nicole,Melcher, Michaela-Christina,Migglautsch, Anna K.,Romauch, Matthias,Schweiger, Martina,Zechner, Rudolf,Zimmermann, Robert
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supporting information
(2020/07/13)
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- Mild Esterification of Carboxylic Acids via Continuous Flow Diazotization of Amines
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A new continuous flow protocol for the diazotization of methylamine with 1,3-propanedinitrite in THF is reported. The synthesis of methyl esters was achieved in high yields from a variety of carboxylic acids in 20 min at 90 °C. Additionally, this protocol was extended to other aryl and alkyl amines, namely secondary amines, to produce various substituted esters in high yield using 2-MeTHF as a solvent. The reaction conditions were compatible with many functional groups, namely nitrogen-containing heterocycles, alkynes, alkenes, alcohols, and phenols. Mechanistic investigations reveal that the reaction appears to proceed through a transient diazonium species rather than a diazo intermediate.
- Audubert, Clément,Lebel, Hélène
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supporting information
p. 4407 - 4410
(2017/08/23)
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- Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo
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Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC50) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and activates B cells.
- Arutla, Viswanath,Leal, Joseph,Liu, Xiaowei,Sokalingam, Sriram,Raleigh, Michael,Adaralegbe, Adejimi,Liu, Li,Pentel, Paul R.,Hecht, Sidney M.,Chang, Yung
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p. 286 - 298
(2017/05/15)
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- METHODS OF RATIONAL NICOTINE HAPTEN DESIGN AND USES THEREOF
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Provided herein are methods for rational design of nicotine haptens. More particularly, provided herein are methods for designing, selecting, and synthesizing nicotine haptens and nicotine hapten conjugates. Also provided herein are novel nicotine haptens and methods for using nicotine haptens to treat nicotine addiction.
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Paragraph 0080
(2017/01/19)
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- Nicotinic acid adenine dinucleotide phosphate analogues substituted on the nicotinic acid and adenine ribosides. Effects on receptormediated Ca2+ release
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Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2+ releasing intracellular second messenger in both mammals and echinoderms. We report that large functionalized substituents introduced at the nicotinic acid 5-position are recognize
- Trabbic, Christopher J.,Zhang, Fan,Walseth, Timothy F.,Slama, James T.
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p. 3593 - 3610
(2015/05/05)
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- NOVEL NICOTINE DNA VACCINES
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The present invention provides DNA-nanostructures comprising and at least one targeting moiety, wherein the at least one targeting moiety is linked to the DNA-nanostructure; and wherein the at least one targeting moiety is nicotine or a nicotine analogue. These compounds elicit an immunogenic response in individuals and are useful as vaccines for ameliorating nicotine dependence.
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Paragraph 0165
(2015/02/18)
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- Synthesis, biologicalevaluation, and molecular modeling of (E)-2-aryl-5-styryl-1,3,4-oxadiazolederivatives as acetylcholine esterase inhibitors
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A library of 2,5-disubstituted 1,3,4-oxadiazole derivatives of (E)-2-aryl-5-(3,4,5-trimethoxystyryl)-1,3,4-oxadiazoles 4(a-o) and (E)-2-aryl-5-(2-benzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazoles 5(a-q) were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. All the synthesized compounds exhibited moderate to good inhibitory activity toward the AChE enzyme. Among the oxadiazole derivatives examined, compounds 4a, 4g, 5c, and 5m (IC50 values of 24.89, 13.72, 37.65, and 19.63 μM, respectively) were found to be promising inhibitors of AChE. Molecular protein-ligand docking studies were examined for these compounds using GOLD docking software and their binding conformations were determined and the simultaneous interactions mode was also established for the potent derivatives. Springer Science+Business Media 2013.
- Kamal, Ahmed,Shaik, Anver Basha,Reddy, G. Narender,Kumar, C. Ganesh,Joseph, Joveeta,Kumar, G. Bharath,Purushotham, Uppula,Sastry, G. Narahari
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p. 2080 - 2092
(2014/05/06)
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- COMPOUNDS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF AMYLOID ASSOCIATED DISEASES
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The invention is in general directed to compounds, such as tannic acid, nicotine, nicotine derivatives and pyrrolidine derivatives of nicotine, and methods for diagnosing, preventing or alleviating the symptoms of amyloid-associated diseases, for example, neuronal diseases, such as, for example, Alzheimer's disease, compounds and methods for inhibiting ion channel activity of beta amyloid, and methods of diagnostic imaging of A/3 fibrils.
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Page/Page column 39-40; 44
(2009/01/24)
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- Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
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The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the Formula (I): wherein R1, R3-R5, A, D, Y and Z are defined herein. The present invention also relates to the discovery that compounds having Formula (I) are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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Page/Page column 16
(2008/06/13)
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- Pyrrolobenzodiazepine pyridine carboxamides and derivatives as follicle-stimulating hormone receptor antagonists
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This invention provides pyrrolobenzodiazepine pyridine carboxamides selected from those of Formula (1), which act as follicle stimulating hormone receptor antagonists. The invention also provides pharmaceutical compositions and methods of treatment utilizing the compounds of Formulae (1) and (2).
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Page/Page column 26
(2010/11/25)
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- 3-(2-Aminoethyl)pyridine analogs as α4β2 nicotinic cholinergic receptor ligands
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An examination of several 3-(2-aminoethyl)pyridine analogs suggests that they likely orient at α4β2 nicotinic cholinergic receptors in a different fashion than their correspondingly substituted nicotine analogs.
- Dukat, Malgorzata,Ramunno, Anna,Banzi, Rita,Damaj, M. Imad,Martin, Billy,Glennon, Richard A.
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p. 4308 - 4312
(2007/10/03)
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- NOVEL COMPOUNDS THAT MODULATE PPARγ TYPE RECEPTORS, AND USE THEREOF IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
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The invention relates to novel compounds corresponding to the general formula (I) below: (I) and also to the method for preparing them, and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, and also in the fields of cardiovascular diseases, immune diseases and/or diseases associated with lipid metabolism),-or alternatively in cosmetic compositions.
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- Syntheses of substituted pyridines, quinolines and diazines via palladium-catalyzed cross-coupling of aryl Grignard reagents
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The palladium-catalyzed cross-coupling reactions between arylmagnesium halides (phenylmagnesium chloride, mesitylmagnesium bromide, 4-(methoxycarbonyl)phenylmagnesium chloride and 4-cyanophenylmagnesium chloride) and halopyridines allowed the synthesis of substituted pyridines. Owing to the remarkably mild conditions used (often below 0°C), the reaction could be extended to the use of functionalized halopyridines, haloquinolines and halodiazines.
- Bonnet, Véronique,Mongin, Florence,Trécourt, Fran?ois,Quéguiner, Guy,Knochel, Paul
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p. 4429 - 4438
(2007/10/03)
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- An immunotherapeutic program for the treatment of nicotine addiction: Hapten design and synthesis
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People continue to smoke and use tobacco products despite well-established hazardous consequences. The most contributing factor is the addictive nature of nicotine. There is no highly effective treatment for the problem of nicotine dependence. Immunotherapy offers an alternative to conventional approaches. The chemistry necessary for a comprehensive immunopharmacological program is presented. Haptens for the generation of antibodies specific for naturally occurring (S)-nicotine, (S)- and (R)-nornicotine, and the metabolite (S)-cotinine were prepared with high optical purity. Preliminary data for antinicotine antibodies are reported.
- Isomura,Wirsching,Janda
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p. 4115 - 4121
(2007/10/03)
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- Piperazine and piperidine compounds
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A group of new piperazine and piperidine compounds having interesting advantageous pharmacological properties and have the formula (a) wherein A represents a heterocyclic group having 5-7 ring atoms wherein 1-3 heteroatoms selected from the group O, N and
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- MODULATORS OF ACETYLCHOLINE RECEPTORS
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The present invention provides a class of pyridine compounds which are modulators of acetylcholine receptors, i.e., compounds which displace acetylcholine receptor ligands from their binding sites. Invention compounds may act as agonists, partial agonists
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- MODULATORS OF ACETYLCHOLINE RECEPTORS
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The present invention provides a class of pyridine compounds which are modulators of acetylcholine receptors, i.e., compounds which displace acetylcholine receptor ligands from their binding sites. Invention compounds may act as agonists, partial agonists
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- MODULATORS OF ACETYLCHOLINE RECEPTORS
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gIn accordance with the present invention, there is provided a class of pyridine compounds which are modulators of acetylcholine receptors. The compounds of the invention displace acetylcholine receptor ligands from their binding sites. Invention compound
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- METHODS FOR THE PREPARATION OF MODULATORS OF ACETYLCHOLINE RECEPTORS
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In accordance with the present invention, there is provided a class of pyridine compounds which are modulators of acetylcholine receptors. The compounds of the invention displace acetylcholine receptor ligands from their binding sites. Invention compounds
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- Modulators of acetylcholine receptors
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In accordance with the present invention, there is provided a class of pyridine compounds which are modulators of acetylcholine receptors. The compounds of the invention displace acetylcholine receptor ligands from their binding sites. Invention compounds
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- A Novel Approach to Dual-Acting Thromboxane Receptor Antagonist/Synthase Inhibitors Based on the Link of 1,3-Dioxane-Thromboxane Receptor Antagonists and -Thromboxane Synthase Inhibitors
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A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel (11) (separately) to thromboxane receptor antagonists (TXRA) from the 1,3-dioxane series, such as ICI 192605 (10).Dual activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 μM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0.The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components.Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg.Thus, (E)-7--4-(2-hydroxyphenyl)-1,3-dioxan-2-yl>benzyl>oxy>phenyl>-7-(3-pyridyl)hept-6-enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 μM)).On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity 64 (rat, 3 h) and >59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation>.Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4percent (rat) and 69 +/- 4.8percent (dog).
- Ackerley, Norman,Brewster, Andrew G.,Brown, George R.,Clarke, David S.,Foubister, Alan J.,et al.
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p. 1608 - 1628
(2007/10/02)
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- PALLADIUM CATALYSED SYNTHESIS OF N AND S HETEROCYCLIC ESTERS
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Palladium catalysed alkoxycarbonylation of heterocyclic halides affords a simple and versatile synthesis of both N and S heterocyclic esters where a range of catalysts have been studied and a method to employ inexpensive inorganic bases has been found.
- Head, Robert A.,Ibbotson, Arthur
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p. 5939 - 5942
(2007/10/02)
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