Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.
Identifieur interne : 002E84 ( Ncbi/Curation ); précédent : 002E83; suivant : 002E85Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.
Auteurs : Jacques Le Roux [France] ; Caroline Leriche [France] ; Philippe Chamiot-Clerc [France] ; John Feutrill [Australie] ; Frank Halley [France] ; David Papin [France] ; Nathalie Derimay [France] ; Christelle Mugler [France] ; Claudine Grépin [France] ; Laurent Schio [France]Source :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2016.
Descripteurs français
- KwdFr :
- AMP cyclique (biosynthèse), Aminoquinoléines (), Humains, Inhibiteurs de la phosphodiestérase-4 (pharmacologie), Inhibiteurs de la phosphodiestérase-4 (synthèse chimique), Lignée cellulaire tumorale, Modèles moléculaires, Pyrazoles (pharmacologie), Pyrazoles (synthèse chimique), Pyrimidines (pharmacologie), Pyrimidines (synthèse chimique), Relation structure-activité, Sulfones (), Sulfones (pharmacologie), Sulfones (synthèse chimique).
- MESH :
- biosynthèse : AMP cyclique.
- pharmacologie : Inhibiteurs de la phosphodiestérase-4, Pyrazoles, Pyrimidines, Sulfones.
- synthèse chimique : Inhibiteurs de la phosphodiestérase-4, Pyrazoles, Pyrimidines, Sulfones.
- Aminoquinoléines, Humains, Lignée cellulaire tumorale, Modèles moléculaires, Relation structure-activité, Sulfones.
English descriptors
- KwdEn :
- Aminoquinolines (chemistry), Cell Line, Tumor, Cyclic AMP (biosynthesis), Humans, Models, Molecular, Phosphodiesterase 4 Inhibitors (chemical synthesis), Phosphodiesterase 4 Inhibitors (pharmacology), Pyrazoles (chemical synthesis), Pyrazoles (pharmacology), Pyrimidines (chemical synthesis), Pyrimidines (pharmacology), Structure-Activity Relationship, Sulfones (chemical synthesis), Sulfones (chemistry), Sulfones (pharmacology).
- MESH :
- chemical , biosynthesis : Cyclic AMP.
- chemical , chemical synthesis : Phosphodiesterase 4 Inhibitors, Pyrazoles, Pyrimidines, Sulfones.
- chemical , chemistry : Aminoquinolines, Sulfones.
- chemical , pharmacology : Phosphodiesterase 4 Inhibitors, Pyrazoles, Pyrimidines, Sulfones.
- Cell Line, Tumor, Humans, Models, Molecular, Structure-Activity Relationship.
Abstract
A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.
DOI: 10.1016/j.bmcl.2015.11.093
PubMed: 26681511
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sortKey="Leriche, Caroline" sort="Leriche, Caroline" uniqKey="Leriche C" first="Caroline" last="Leriche">Caroline Leriche</name><affiliation wicri:level="3"><nlm:affiliation>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Chamiot Clerc, Philippe" sort="Chamiot Clerc, Philippe" uniqKey="Chamiot Clerc P" first="Philippe" last="Chamiot-Clerc">Philippe Chamiot-Clerc</name><affiliation wicri:level="3"><nlm:affiliation>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Feutrill, John" sort="Feutrill, John" uniqKey="Feutrill J" first="John" last="Feutrill">John Feutrill</name><affiliation wicri:level="1"><nlm:affiliation>SYN|thesis Med Chem, 399 Royal Parade, Parkville, VIC 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>SYN|thesis Med Chem, 399 Royal Parade, Parkville, VIC 3052</wicri:regionArea><wicri:noRegion>VIC 3052</wicri:noRegion></affiliation></author><author><name sortKey="Halley, Frank" sort="Halley, Frank" uniqKey="Halley F" first="Frank" last="Halley">Frank Halley</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France. Electronic address: frank.halley@sanofi.com.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine</wicri:regionArea><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion></affiliation></author><author><name sortKey="Papin, David" sort="Papin, David" uniqKey="Papin D" first="David" last="Papin">David Papin</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine</wicri:regionArea><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion></affiliation></author><author><name sortKey="Derimay, Nathalie" sort="Derimay, Nathalie" uniqKey="Derimay N" first="Nathalie" last="Derimay">Nathalie Derimay</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg</wicri:regionArea><wicri:noRegion>67000 Strasbourg</wicri:noRegion><placeName><settlement type="city">Strasbourg</settlement><region type="region" nuts="2">Grand Est</region><region type="old region" nuts="2">Alsace (région administrative)</region></placeName></affiliation></author><author><name sortKey="Mugler, Christelle" sort="Mugler, Christelle" uniqKey="Mugler C" first="Christelle" last="Mugler">Christelle Mugler</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg</wicri:regionArea><wicri:noRegion>67000 Strasbourg</wicri:noRegion><placeName><settlement type="city">Strasbourg</settlement><region type="region" nuts="2">Grand Est</region><region type="old region" nuts="2">Alsace (région administrative)</region></placeName></affiliation></author><author><name sortKey="Grepin, Claudine" sort="Grepin, Claudine" uniqKey="Grepin C" first="Claudine" last="Grépin">Claudine Grépin</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris</wicri:regionArea><wicri:noRegion>75012 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Schio, Laurent" sort="Schio, Laurent" uniqKey="Schio L" first="Laurent" last="Schio">Laurent Schio</name><affiliation wicri:level="1"><nlm:affiliation>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine</wicri:regionArea><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion><wicri:noRegion>94400 Vitry-sur-Seine</wicri:noRegion></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aminoquinolines (chemistry)</term><term>Cell Line, Tumor</term><term>Cyclic AMP (biosynthesis)</term><term>Humans</term><term>Models, Molecular</term><term>Phosphodiesterase 4 Inhibitors (chemical synthesis)</term><term>Phosphodiesterase 4 Inhibitors (pharmacology)</term><term>Pyrazoles (chemical synthesis)</term><term>Pyrazoles (pharmacology)</term><term>Pyrimidines (chemical synthesis)</term><term>Pyrimidines (pharmacology)</term><term>Structure-Activity Relationship</term><term>Sulfones (chemical synthesis)</term><term>Sulfones (chemistry)</term><term>Sulfones (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>AMP cyclique (biosynthèse)</term><term>Aminoquinoléines ()</term><term>Humains</term><term>Inhibiteurs de la phosphodiestérase-4 (pharmacologie)</term><term>Inhibiteurs de la phosphodiestérase-4 (synthèse chimique)</term><term>Lignée cellulaire tumorale</term><term>Modèles moléculaires</term><term>Pyrazoles (pharmacologie)</term><term>Pyrazoles (synthèse chimique)</term><term>Pyrimidines (pharmacologie)</term><term>Pyrimidines (synthèse chimique)</term><term>Relation structure-activité</term><term>Sulfones ()</term><term>Sulfones (pharmacologie)</term><term>Sulfones (synthèse chimique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Cyclic AMP</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Phosphodiesterase 4 Inhibitors</term><term>Pyrazoles</term><term>Pyrimidines</term><term>Sulfones</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Aminoquinolines</term><term>Sulfones</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Phosphodiesterase 4 Inhibitors</term><term>Pyrazoles</term><term>Pyrimidines</term><term>Sulfones</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>AMP cyclique</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la phosphodiestérase-4</term><term>Pyrazoles</term><term>Pyrimidines</term><term>Sulfones</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de la phosphodiestérase-4</term><term>Pyrazoles</term><term>Pyrimidines</term><term>Sulfones</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Models, Molecular</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Aminoquinoléines</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Modèles moléculaires</term><term>Relation structure-activité</term><term>Sulfones</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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