Drug Discovery; Medicinal Chemistry; Synthesis; Pharmacology
Abstract :
[en] The present work describes the synthesis and the biological evaluation of novel compounds acting as pyruvate dehydrogenase kinase (PDK) inhibitors. These drugs should become a new therapeutic approach for the treatment of pathologies improved by the control of the blood lactate level.
Methods:
Four series of compounds belonging to N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides and to 1,2,4-benzothiadiazine 1,1-dioxides were prepared and evaluated as PDK inhibitors.
Results:
The newly synthesized N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides structurally related to previously reported reference compounds 4 and 5 were found to be potent PDK inhibitors (i.e. 10d: IC50 = 41 nM). 1,2,4-Benzothiadiazine 1,1-dioxides carrying a (methyl/trifluoromethyl)-propanamide moiety at the 6-position were also designed as conformationally restricted ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides. Most of them were found to be less potent than their ring-opened analogues. Interestingly, the best choice of hydrocarbon side chain at the 4-position was the benzyl chain, providing 11c (IC50 = 3.6 µM) belonging to “unsaturated” 1,2,4-benzothiadiazine 1,1-dioxides, and 12c (IC50 = 0.5 µM) belonging to “saturated’ 1,2,4-benzothiadiazine 1,1-dioxides.
Conclusion:
This work showed that ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides were less active as PDK inhibitors than their corresponding ring-opened analogues. However, the introduction of a bulkier substituent at the 4-position of the 1,2,4-benzothiadiazine 1,1-dioxide core structure, such as a benzyl or a phenethyl side chain, was allowed, opening the way to the design of new inhibitors with improved PDK inhibitory activity.
Research Center/Unit :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Arslan, Deniz ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Schoumacher, Matthieu ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Dilly, Sébastien ; Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-Research
Elmoualij, Benaïssa ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Zorzi, Danièle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Quatresooz, Pascale ; Centre Hospitalier Universitaire de Liège - CHU > > Service dermatopathologie
Lambert, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'ophtalmologie
Noël, Agnès ; Université de Liège - ULiège > GIGA > GIGA Cancer
Pirotte, Bernard ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
De Tullio, Pascal ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Language :
English
Title :
Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors
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