2 Aminopyridine

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Richard B. Silverman - One of the best experts on this subject based on the ideXlab platform.

  • improvement of cell permeability of human neuronal nitric oxide synthase inhibitors using potent and selective 2 Aminopyridine based scaffolds with a fluorobenzene linker
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Heng Yen Wang, Georges Chreifi, Thomas L Poulos, Richard B. Silverman
    Abstract:

    Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-Aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA–BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-Aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respect...

  • Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2‑Aminopyridine-Based Scaffolds with a Fluorobenzene Linker
    2017
    Co-Authors: Heng Yen Wang, Georges Chreifi, Thomas L Poulos, Richard B. Silverman
    Abstract:

    Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-Aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA–BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-Aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively

  • Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase
    Beilstein journal of organic chemistry, 2009
    Co-Authors: Graham R. Lawton, Pavel Martásek, Linda J. Roman, Richard B. Silverman
    Abstract:

    Highly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-Aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the Aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the Aminopyridine ring, and so the molecule will carry a lower net charge. This could lead to an increased ability to cross the blood-brain barrier thereby increasing the in vivo potency of these compounds. The 2-aminothiazole-based compound was less potent than the 2-Aminopyridine-based analogue. 4-Aminothiazoles were unstable in water, undergoing tautomerization and hydrolysis to give inactive thiazolones.

Jianping Lang - One of the best experts on this subject based on the ideXlab platform.

Gregory D. Cuny - One of the best experts on this subject based on the ideXlab platform.

  • receptor interacting protein kinase 2 ripk2 and nucleotide binding oligomerization domain nod cell signaling inhibitors based on a 3 5 diphenyl 2 Aminopyridine scaffold
    European Journal of Medicinal Chemistry, 2020
    Co-Authors: Chalada Suebsuwong, Alex N Bullock, Bing Dai, Daniel M Pinkas, Anantha Lakshmi Duddupudi, Joshua C Bufton, Lisa Schlicher, Mads Gyrdhansen, Alexei Degterev, Gregory D. Cuny
    Abstract:

    Abstract Receptor-interacting protein kinase 2 (RIPK2) is a key mediator of nucleotide-binding oligomerization domain (NOD) cell signaling that has been implicated in various chronic inflammatory conditions. A new class of RIPK2 kinase/NOD signaling inhibitors based on a 3,5-diphenyl-2-Aminopyridine scaffold was developed. Several co-crystal structures of RIPK2•inhibitor complexes were analyzed to provide insights into inhibitor selectivity versus the structurally related activin receptor-like kinase 2 (ALK2) demonstrating that the inhibitor sits deeper in the hydrophobic binding pocket of RIPK2 perturbing the orientation of the DFG motif. In addition, the structure-activity relationship study revealed that in addition to anchoring to the hinge and DFG via the 2-Aminopyridine and 3-phenylsulfonamide, respectively, appropriate occupancy of the region between the gatekeeper and the αC-helix provided by substituents in the 4- and 5-positions of the 3-phenylsulfonamide were necessary to achieve potent NOD cell signaling inhibition. For example, compound 18t (e.g. CSLP37) displayed potent biochemical RIPK2 kinase inhibition (IC50 = 16 ± 5 nM), >20-fold selectivity versus ALK2 and potent NOD cell signaling inhibition (IC50 = 26 ± 4 nM) in the HEKBlue assay. Finally, in vitro ADME and pharmacokinetic characterization of 18t further supports the prospects of the 3,5-diphenyl-2-Aminopyridine scaffold for the generation of in vivo pharmacology probes of RIPK2 kinase and NOD cell signaling functions.

  • Structure–Activity Relationship of 3,5-Diaryl-2-Aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants
    2015
    Co-Authors: Ah Mohedas, Alex N Bullock, Ce Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-Aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG

  • structure activity relationship of 3 5 diaryl 2 Aminopyridine alk2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ah Mohedas, Alex N Bullock, Ce Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-Aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity...

Alejandro Romero - One of the best experts on this subject based on the ideXlab platform.

  • cholinergic and neuroprotective drugs for the treatment of alzheimer and neuronal vascular diseases ii synthesis biological assessment and molecular modelling of new tacrine analogues from highly substituted 2 Aminopyridine 3 carbonitriles
    Bioorganic & Medicinal Chemistry, 2011
    Co-Authors: Abdelouahid Samadi, Carolina Valderas, Cristobal De Los Rios, Agatha Bastida, Mourad Chioua, Laura Gonzalezlafuente, Ines Colmena, Luis Gandia, Alejandro Romero
    Abstract:

    Abstract The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11–22 is described. Compounds 11–22 have been obtained by Friedlander-type reaction of 2-Aminopyridine-3-carbonitriles 1–10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC50 (EeAChE: 14 nM); IC50 (eqBuChE: 5.2 μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC50 (EeAChE: 64 nM); IC50 (eqBuChE: 9.6 μM] showed that this compound is a mixed-type inhibitor (Ki = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11–22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K+-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11–22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.

  • multipotent drugs with cholinergic and neuroprotective properties for the treatment of alzheimer and neuronal vascular diseases i synthesis biological assessment and molecular modeling of simple and readily available 2 Aminopyridine and 2 chloropyridine 3 5 dicarbonitriles
    Bioorganic & Medicinal Chemistry, 2010
    Co-Authors: Abdelouahid Samadi, Mourad Chioua, Laura Gonzalezlafuente, Luis Gandia, Alejandro Romero, Jose Marcocontelles, Elena Soriano, Monica Alvarezperez, J M Roda, Manuela G Lopez
    Abstract:

    The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-Aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8-31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.

Abdelouahid Samadi - One of the best experts on this subject based on the ideXlab platform.

  • microwave irradiation assisted amination of 2 chloropyridine derivatives with amide solvents
    Synthetic Communications, 2011
    Co-Authors: Abdelouahid Samadi, Mourad Chioua, D J Silva, Maria Do Carmo Carreiras, Jose Marcocontelles
    Abstract:

    Abstract A simple, quick, and high-yielding microwave-assisted synthesis of 2-(N,N-dimethyl)amine- and 2-Aminopyridine derivatives is reported here for the first time in the reaction of 2-chloro substituted pyridines with amide solvents such as dimethylformamide or formamide, without transition-metal catalysts.

  • cholinergic and neuroprotective drugs for the treatment of alzheimer and neuronal vascular diseases ii synthesis biological assessment and molecular modelling of new tacrine analogues from highly substituted 2 Aminopyridine 3 carbonitriles
    Bioorganic & Medicinal Chemistry, 2011
    Co-Authors: Abdelouahid Samadi, Carolina Valderas, Cristobal De Los Rios, Agatha Bastida, Mourad Chioua, Laura Gonzalezlafuente, Ines Colmena, Luis Gandia, Alejandro Romero
    Abstract:

    Abstract The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11–22 is described. Compounds 11–22 have been obtained by Friedlander-type reaction of 2-Aminopyridine-3-carbonitriles 1–10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC50 (EeAChE: 14 nM); IC50 (eqBuChE: 5.2 μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC50 (EeAChE: 64 nM); IC50 (eqBuChE: 9.6 μM] showed that this compound is a mixed-type inhibitor (Ki = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11–22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K+-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11–22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.

  • multipotent drugs with cholinergic and neuroprotective properties for the treatment of alzheimer and neuronal vascular diseases i synthesis biological assessment and molecular modeling of simple and readily available 2 Aminopyridine and 2 chloropyridine 3 5 dicarbonitriles
    Bioorganic & Medicinal Chemistry, 2010
    Co-Authors: Abdelouahid Samadi, Mourad Chioua, Laura Gonzalezlafuente, Luis Gandia, Alejandro Romero, Jose Marcocontelles, Elena Soriano, Monica Alvarezperez, J M Roda, Manuela G Lopez
    Abstract:

    The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-Aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8-31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.

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