ABSTRACT
The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Animals , Biological Availability , Disease Models, Animal , Half-Life , Humans , I-kappa B Kinase/metabolism , Indoles/chemical synthesis , Indoles/pharmacokinetics , Lung/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Subject(s)
Chemistry, Pharmaceutical/methods , I-kappa B Kinase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Adenosine Triphosphate/chemistry , Binding Sites , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.