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Acta Crystallographica. Section C,... Feb 2002The title compound, C(5)H(6)N(2)S, is a simple but novel pyridinethiol of pharmacological interest. The molecule is planar. The crystal packing is dominated by...
The title compound, C(5)H(6)N(2)S, is a simple but novel pyridinethiol of pharmacological interest. The molecule is planar. The crystal packing is dominated by hydrophobic contacts and a pair of hydrogen-bond interactions between the amino group of one pyridine molecule and the ring N atom of a neighbouring base, stabilizing the structure.
Topics: Aminopyridines; Crystallography, X-Ray; Hydrogen Bonding; Models, Molecular; Molecular Structure; Schistosomicides; Sulfhydryl Compounds; Trypanocidal Agents
PubMed: 11828114
DOI: 10.1107/s0108270101020352 -
Steroids Nov 2016The synthesis of novel steroidal 3-cyano-2-aminopyridines using enaminonitrile and various primary amines was established under solvent-free condition. Structures of the...
The synthesis of novel steroidal 3-cyano-2-aminopyridines using enaminonitrile and various primary amines was established under solvent-free condition. Structures of the new compounds were characterized by MS, H and C NMR data and the structure of 2-aminopyridine of the product 5b was further confirmed by X-ray analysis. The reaction mechanism was proposed on the basis of the key intermediate obtained. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.
Topics: Aminopyridines; Crystallography, X-Ray; Heterocyclic Compounds, 2-Ring; Molecular Structure; Nitriles; Solvents; Steroids
PubMed: 27639101
DOI: 10.1016/j.steroids.2016.09.005 -
European Journal of Medicinal Chemistry Dec 2019Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In...
Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALK and ALK mutants with IC values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants.
Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Cell Line, Tumor; Cell Survival; Crizotinib; Drug Resistance, Neoplasm; Humans; Mutation; Protein Kinase Inhibitors; Pyridones
PubMed: 31569004
DOI: 10.1016/j.ejmech.2019.111734 -
Bioorganic & Medicinal Chemistry Mar 2015The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic,...
The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50=6.9μM) and 7h (IC50=12.2μM) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure- and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases.
Topics: Aminopyridines; Computer-Aided Design; Drug Discovery; Drug Evaluation, Preclinical; HT29 Cells; Humans; Inhibitory Concentration 50; Janus Kinase 2; Protein Kinase Inhibitors
PubMed: 25650310
DOI: 10.1016/j.bmc.2015.01.016 -
The Journal of Organic Chemistry Mar 2014A practical and efficient method for the synthesis of substituted 2-aminopyridines from pyridine N-oxides is reported. Yields of purified, isolated products of up to 84%...
A practical and efficient method for the synthesis of substituted 2-aminopyridines from pyridine N-oxides is reported. Yields of purified, isolated products of up to 84% are observed for the one-pot, two-step process. The reaction involves an in situ deprotection of an isolable N-formylaminopyridine intermediate and facilitates the synthesis of 2-aminopyridines for which other methods fail.
Topics: Aminopyridines; Cyanides; Molecular Structure; Pyridines
PubMed: 24490824
DOI: 10.1021/jo402693s -
Clinical Pharmacology and Therapeutics May 1982Nine healthy subjects (7 men; 2 women) received single 20-mg IV injections of 4-aminopyridine (4-AP). Six of the subjects received the same dose in the form of...
Nine healthy subjects (7 men; 2 women) received single 20-mg IV injections of 4-aminopyridine (4-AP). Six of the subjects received the same dose in the form of enteric-coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4-AP using a high-performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 +/- 0.9 (mean +/- SD) 1 kg-1, the terminal half-life (t 1/2) 3.6 +/- 0.9 hr, and the total serum clearance 0.61 +/- 0.14 1 hr-1 kg-1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t 1/2 and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4-AP was 90.6 +/- 7.8% after intravenous doses and 88.5 +/- 4.8% after oral doses of enteric-coated tablets. The bioavailability of the enteric-coated tablets calculated from the area under the serum concentration curve (95 +/- 29%) did not differ from that calculated from urinary excretion (98 +/- 8%). Protein binding of 4-AP was found to be negligible. Biotransformation is unlikely.
Topics: 4-Aminopyridine; Administration, Oral; Adolescent; Adult; Aminopyridines; Blood Proteins; Female; Humans; Injections, Intravenous; Kinetics; Male; Protein Binding; Saliva
PubMed: 7075108
DOI: 10.1038/clpt.1982.82 -
Chemical Communications (Cambridge,... Jan 20222-Aminopyridine is a simple, low molecular weight and perfectly functionalised moiety known for the synthesis of diverse biological molecules. Many pharmaceutical... (Review)
Review
2-Aminopyridine is a simple, low molecular weight and perfectly functionalised moiety known for the synthesis of diverse biological molecules. Many pharmaceutical companies across the globe aim to synthesise low-molecular weight molecules for use as pharmacophores against various biological targets. 2-Aminopyridine can serve as a perfect locomotive in the synthesis and pulling of such molecules towards respective pharmacological goals. The major advantage of this moiety is its simple design, which can be used to produce single products with minimum side reactions. Moreover, the exact weight of synthesised compounds is low, which enables facile identification of toxicity-causing metabolites in drug discovery programmes. This manuscript is a quick review of such pharmacophores derived from 2-aminopyridine.
Topics: Aminopyridines; Drug Discovery; Molecular Structure
PubMed: 34904599
DOI: 10.1039/d1cc04602k -
Journal of Medicinal Chemistry Jul 2015We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine...
We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.
Topics: Aminopyridines; Animals; Biological Availability; Enzyme Inhibitors; Humans; Male; Mice; Models, Molecular; Nitric Oxide Synthase Type I; Protein Conformation; Rats; Structure-Activity Relationship; Substrate Specificity
PubMed: 26120733
DOI: 10.1021/acs.jmedchem.5b00573 -
Journal of Medicinal Chemistry Apr 2011We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal...
We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal structures of leads 1 and 2 (Delker, S. L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R. B.; Poulos, T. L. Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of cerebral palsy . J. Am. Chem. Soc. 2010, 132, 5437-5442) and synthesized using a highly efficient route. The best inhibitor, 3j, showed low nanomolar inhibitory potency and modest isoform selectivity. It also exhibited enhanced membrane permeability. Inhibitor 3j binds to both the substrate site and the pterin site in nNOS but only to the substrate site in eNOS. These compounds provide a basis for further development of novel, potent, isoform selective, and bioavailable inhibitors for nNOS.
Topics: Aminopyridines; Animals; Cattle; Cell Membrane Permeability; Drug Design; Enzyme Inhibitors; HEK293 Cells; Humans; Mice; Models, Molecular; Nitric Oxide Synthase Type I; Protein Conformation; Rats
PubMed: 21410186
DOI: 10.1021/jm101071n -
Biochimica Et Biophysica Acta Nov 1990Aminopyridines belong to the class of compounds which facilitate synaptic transmission at low calcium concentration, an effect associated with the block of K+ channels,...
Aminopyridines belong to the class of compounds which facilitate synaptic transmission at low calcium concentration, an effect associated with the block of K+ channels, enhanced entry of calcium into presynaptic terminals and greater release of transmitter. We have measured the zeta-potential of phosphatidylserine vesicles in the presence of aminopyridines and some related compounds in order to relate the strength of association of the aminopyridines with their biological effectiveness. The dependence of zeta-potential on the concentration of aminopyridines was analyzed in terms of the Langmuir-Stern-Grahame adsorption model. The rank order of the association constants (in M-1) obtained in the study was as follows: 3,4-diaminopyridine (6.5), 4,5-diaminopyrimidine (3.8), 4-aminopyridine (2.6), 3-aminopyridine (1.8), 2-aminopyridine (1.6), 4-dimethylaminopyridine (0.5), 4-aminopyridine methiodide (0.2), and, as control, calcium (12.1). The comparison of association constants with published results of the electric potential maps obtained by the CNDO/2 method suggests that binding to phosphatidylserine membrane increases with the density of excess charge on the protonated aminopyridine ring. We find that the sequence of potencies of aminopyridines in blocking K+ channels, in releasing transmitter, and in the shifts of calcium concentration dependence of synaptic transmission are about the same as the sequence of association constants with the phosphatidylserine membrane. Assuming that the binding domain for aminopyridines in the presynaptic terminal has similar adsorption properties as the phosphatidylserine membrane, we estimate the electric potential difference between the domain and the external solution to be between -300 and -340 mV.
Topics: Adsorption; Aminopyridines; Animals; Calcium; Cattle; Hydrogen-Ion Concentration; Phosphatidylserines; Structure-Activity Relationship; Synaptic Membranes; Synaptic Transmission
PubMed: 2173955
DOI: 10.1016/0005-2736(90)90162-h