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Bioorganic & Medicinal Chemistry Letters Apr 2010The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small...
The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.
Topics: Alzheimer Disease; Aminopyridines; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Brain; Crystallography, X-Ray; Humans; Models, Molecular; Structure-Activity Relationship
PubMed: 20223661
DOI: 10.1016/j.bmcl.2010.02.075 -
Organic Letters Apr 2011Bimolecular cobalt-catalyzed [2 + 2 + 2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100% yield. The high...
Bimolecular cobalt-catalyzed [2 + 2 + 2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100% yield. The high regioselectivity observed depends on the substitution pattern at the starting ynamide. Aminopyridines bearing TMS and Ts groups are efficiently deprotected in an orthogonal fashion.
Topics: 4-Aminopyridine; Aminopyridines; Bridged Bicyclo Compounds, Heterocyclic; Catalysis; Cobalt; Models, Molecular; Molecular Structure; Stereoisomerism
PubMed: 21413688
DOI: 10.1021/ol200417p -
Steroids Feb 2011Microwave (MW) assisted synthesis and solid state structural characterizations of novel lithocholyl amides of 2-, 3-, and 4-aminopyridine are reported. It is shown that...
Microwave (MW) assisted synthesis and solid state structural characterizations of novel lithocholyl amides of 2-, 3-, and 4-aminopyridine are reported. It is shown that the MW technique is a proper method in the preparation of N-lithocholyl amides of isomeric aminopyridines. It offers many advantages compared to conventional heating. The molecular and crystal structures as well as the polymorphic and hydrated forms of prepared conjugates with their thermodynamic stabilities have been characterized by means of high resolution liquid- and solid-state NMR spectroscopy, single crystal and powder X-ray diffraction, and thermogravimetric analysis. Owing to the many biological functions of bile acids and amino substituted nitrogen heterocycles, knowledge of the crystal packing of these novel conjugates may have relevance for potential pharmaceutical applications.
Topics: Amides; Aminopyridines; Crystallization; Isomerism; Lithocholic Acid; Magnetic Resonance Spectroscopy; Microwaves; Thermogravimetry; X-Ray Diffraction
PubMed: 21130795
DOI: 10.1016/j.steroids.2010.11.007 -
Organic Letters Nov 2010A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to...
A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to S(N)Ar chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses the phosphonium salt, PyBroP, as a means of substrate activation.
Topics: Amination; Amines; Aminopyridines; Combinatorial Chemistry Techniques; Molecular Structure; Organophosphorus Compounds; Pyridines
PubMed: 20958085
DOI: 10.1021/ol102301u -
The Journal of Organic Chemistry Sep 2012Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted 2-aminopyridines in an atom-efficient manner that is both high...
Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted 2-aminopyridines in an atom-efficient manner that is both high yielding and regioselective. This system was also used to cyclize two terminal alkynes and a cyanamide to afford a 2,4,6-trisubstituted pyridine product regioselectively.
Topics: Aminopyridines; Catalysis; Cyanamide; Cyclization; Diynes; Iron; Molecular Structure
PubMed: 22845666
DOI: 10.1021/jo3012418 -
Journal of Molecular Modeling May 2007We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K(+) channels. Several active...
We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K(+) channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the alpha-subunit of the K(+) channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K(+) channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3-7 kcal mol(-1). On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.
Topics: Aminopyridines; Bacterial Proteins; Crystallography, X-Ray; Hydrogen-Ion Concentration; Potassium Channels; Potassium Channels, Voltage-Gated; Protein Binding; Protein Structure, Secondary; Protein Transport
PubMed: 17340113
DOI: 10.1007/s00894-007-0184-9 -
Journal of Medicinal Chemistry Dec 2012In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were...
In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
Topics: Administration, Oral; Aminopyridines; Animals; Antimalarials; Drug Resistance, Multiple; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Malaria; Mice; Microsomes, Liver; Plasmodium berghei; Plasmodium falciparum; Solubility; Structure-Activity Relationship
PubMed: 23189922
DOI: 10.1021/jm301476b -
Biophysical Chemistry Apr 2002This work presents a theoretical study aimed at the identification of the receptor site for the blocking of the voltage dependent K+ channels by protonated...
This work presents a theoretical study aimed at the identification of the receptor site for the blocking of the voltage dependent K+ channels by protonated aminopyridines. Thus, the density functional theory (DFT) at the B3LYP/6-311 G (d,p) level is applied, both in vacuum and in solution, to a series of active (protonated) compounds: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. Analysis of the X-ray structure of the alpha-subunit of the channel shows that charged aminopyridines can interact electrostatically with a glutamic acid residue in the outside of the pore, or through a cation-pi interaction in the inside. To test both possibilities, model complexes are built using as nucleophiles a carboxylic group and an ethylene molecule, respectively. The three-dimensional electrostatic potential distribution of the protonated aminopyridines shows that an approaching nucleophile will be oriented toward the N-H (protonated) bond. Interaction with the carboxylic residue leads to a proton transfer, with the aminopyridine-carboxylic acid linked by a hydrogen bond. The observed breaking of the equivalence of the Laplacian of the charge density, the relative energy variation for the complexes, and the interaction with only one of the carboxylic residues in the fourfold alpha-subunit of the K+ channel are not compatible with the observed in vitro activity variation of aminopyridines. On the other hand, the study on the ethylene complexes shows, in vacuum and solution, a cation-pi interaction, clearly characterized by the atoms in molecules (AIM) theory. The variation of relative energy in solution is very small, but approaches the variation of in vitro activity. Our results, the pharmacophoric characteristics of aminopyridines, and the analysis of the three-dimensional internal structure of the K+ channel alpha-subunit suggest two putative receptor sites. One is formed by the four Thr-Thr-Val chains conforming the entrance to the narrow part of the inner K+ channel. The other is defined by four Thr residues within the pore.
Topics: Amino Acid Sequence; Aminopyridines; Binding Sites; Models, Chemical; Models, Molecular; Molecular Sequence Data; Potassium Channels, Voltage-Gated; Static Electricity; Thermodynamics
PubMed: 11975989
DOI: 10.1016/s0301-4622(02)00002-9 -
Journal of Pharmaceutical Sciences Aug 1988O-Demethylation of pyrilamine with l-propanethiol and potassium tert-butoxide gave hydroxytripelennamine, one of the major metabolites of tripelennamine. The reaction of...
O-Demethylation of pyrilamine with l-propanethiol and potassium tert-butoxide gave hydroxytripelennamine, one of the major metabolites of tripelennamine. The reaction of pyrilamine with other demethylating agents has been explored and the products formed have been characterized. The reaction of pyrilamine with 48% hydrobromic acid yielded 2-(2-dimethylaminoethyl)aminopyridine. When a mild, neutral demethylating agent, Me3Sil, was used, 2,3-dihydroimidazopyridinium iodide was the sole product formed.
Topics: Acids; Aminopyridines; Chemical Phenomena; Chemistry; Dealkylation; Hydrobromic Acid; Pyrilamine
PubMed: 2850359
DOI: 10.1002/jps.2600770818 -
Biophysical Chemistry Nov 2006This work presents a study aimed at the theoretical prediction of pK(a) values of aminopyridines, as a factor responsible for the activity of these compounds as blockers...
This work presents a study aimed at the theoretical prediction of pK(a) values of aminopyridines, as a factor responsible for the activity of these compounds as blockers of the voltage-dependent K(+) channels. To cover a large range of pK(a) values, a total of seven substituted pyridines is considered as a calibration set: pyridine, 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 2-chloropyridine, 3-chloropyridine, and 4-methylpirydine. Using ab initio G1, G2 and G3 extrapolation methods, and the CPCM variant of the Polarizable Continuum Model for solvation, we calculate gas phase and solvation free energies. pK(a) values are obtained from these data using a thermodynamic cycle for describing protonation in aqueous and gas phases. The results show that the relatively inexpensive G1 level of theory is the most accurate at predicting pK(a) values in aminopyridines. The highest standard deviation with respect to the experimental data is 0.69 pK(a) units for absolute values calculations. The difference increases slightly to 0.74 pK(a) units when the pK(a) is computed relative to the pyridine molecule. Considering only compounds at least as basic as pyridine (the values of interest for bioactive aminopyridines) the error falls to 0.10 and 0.12 pK(a) units for the absolute and relative computations, respectively. The technique can be used to predict the effect of electronegative substituents in the pK(a) of 4-AP, the most active aminopyridine considered in this work. Thus, 2-chloro and 3-chloro-4-aminopyridine are taken into account. The results show a decrease of the pK(a), suggesting that these compounds are less active than 4-AP at blocking the K(+) channel.
Topics: Aminopyridines; Forecasting; Hydrogen-Ion Concentration; Models, Theoretical; Thermodynamics
PubMed: 16844281
DOI: 10.1016/j.bpc.2006.06.007