The Experts below are selected from a list of 975 Experts worldwide ranked by ideXlab platform
David R. Adams - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase inhibitors part 1 synthesis and structure activity relationships of Pyrazolopyridine pyridazinone pde inhibitors developed from ibudilast
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. AdamsAbstract:Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the Pyrazolopyridine. Migration of the pyridazinone ring connection from the Pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
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Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of Pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. AdamsAbstract:Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the Pyrazolopyridine. Migration of the pyridazinone ring connection from the Pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
Masaaki Toda - One of the best experts on this subject based on the ideXlab platform.
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Orally active PDE4 inhibitors with therapeutic potential.
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Hiroshi Ochiai, Tazumi Ohtani, Akiharu Ishida, Katuya Kishikawa, Takaaki Obata, Hisao Nakai, Masaaki TodaAbstract:Structural optimization of Pyrazolopyridine derivative 2, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was carried out successfully. The process of discovery of new orally active PDE4 inhibitors, which are expected to possess therapeutic potential, is presented and their structure-activity relationships are discussed.
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New orally active PDE4 inhibitors with therapeutic potential.
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Hiroshi Ochiai, Tazumi Ohtani, Akiharu Ishida, Katuya Kishikawa, Takaaki Obata, Hisao Nakai, Kensuke Kusumi, Masaaki TodaAbstract:Structural optimization of Pyrazolopyridine derivative 2, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was carried out successfully. The process of discovery of new orally active PDE4 inhibitors, which are expected to possess therapeutic potential, is presented and their structure-activity relationships are discussed.
Robert W. Allcock - One of the best experts on this subject based on the ideXlab platform.
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phosphodiesterase inhibitors part 1 synthesis and structure activity relationships of Pyrazolopyridine pyridazinone pde inhibitors developed from ibudilast
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. AdamsAbstract:Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the Pyrazolopyridine. Migration of the pyridazinone ring connection from the Pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
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Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of Pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. AdamsAbstract:Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the Pyrazolopyridine. Migration of the pyridazinone ring connection from the Pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
Kirk L. Stevens - One of the best experts on this subject based on the ideXlab platform.
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Organic Syntheses - Synthesis of Pyrazolo[1,5‐a]Pyridines Via Azirines: Preparation of 2‐(3‐Bromophenyl)‐6‐(Trifluoromethyl)Pyrazolo[1,5‐a]Pyridine
Organic Syntheses, 2009Co-Authors: Stephen N. Greszler, Kirk L. StevensAbstract:3'-Bromoacetophenone Sodium hydride 2-Chloro-5-(trifluoromethyl)pyridine Trifluoracetic anhydride Keywords: pyridines; hydroxylamine hydrochloride; azirines; Pyrazolopyridines; heterocycles; heating caution; azirine intermediates; intramolecular reactions; waste disposal; safety
Tomoshige Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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A Short and Efficient Synthesis of a Chiral Pyridazinone Derivative by the Chiral-Pool Method
Synthesis, 2004Co-Authors: Noriyuki Yoshida, Katsuya Awano, Tomoshige Kobayashi, Kunihide FujimoriAbstract:The asymmetric synthesis of a (R)-4,5-dihydro-5-methylpyridazin-3(2H)-one derivative bearing a Pyrazolopyridine ring, which is a potent inhibitor of phosphodiesterase, was achieved with a high optical yield in four steps starting from (R)-2-chloropropionyl chloride by a chiral-pool method.
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Enantioselective synthesis of a chiral pyridazinone derivative by lipase-catalyzed hydrolysis
Tetrahedron: Asymmetry, 2003Co-Authors: Noriyuki Yoshida, Masahiro Aono, Takeshi Tsubuki, Katsuya Awano, Tomoshige KobayashiAbstract:The lipase-catalyzed resolution of 2-(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-one derivatives in organic solvents containing water was demonstrated to be a practical method for the synthesis of a chiral pyridazinone bearing a Pyrazolopyridine ring, which is a potent phosphodiesterase inhibitor.
