RÉSUMÉ
Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
Sujet(s)
Antinéoplasiques/synthèse chimique , Protéines proto-oncogènes c-mdm2/antagonistes et inhibiteurs , Pyrrolidines/synthèse chimique , Protéine p53 suppresseur de tumeur/antagonistes et inhibiteurs , para-Aminobenzoates/synthèse chimique , Animaux , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Découverte de médicament , Humains , Mâle , Souris , Souris de lignée C57BL , Pyrrolidines/pharmacologie , Pyrrolidines/usage thérapeutique , para-Aminobenzoates/pharmacologie , para-Aminobenzoates/usage thérapeutiqueRÉSUMÉ
A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.