ABSTRACT
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.
Subject(s)
Benzamides/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Models, Molecular , Structure-Activity RelationshipABSTRACT
The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.
ABSTRACT
A multicomponent assembly of pyrido-fused tetrahydroquinolines is accomplished in a one-pot process from the interaction of dihydroazines, aldehydes, and anilines. A rational screening of the different components and parameters of this reaction, such as the range of reactive starting materials, catalysts and reaction conditions (solvent range; thermal, high pressure- and microwave-promoted processes) is carried out. Optimized conditions allow an efficient preparation of pyrido-fused tetrahydroquinolines with good yields, bypassing the biomimetic NADH-like reductive pathway which is typical in the interaction of dihydropyridines with carbonyl compounds and amines. Furthermore, solid-supported versions of the process have been developed, which should facilitate the preparation of libraries.
Subject(s)
Hydrogen/chemistry , Pyridones/chemistry , Quinolines/chemistry , Quinolines/chemical synthesis , Aldehydes/chemistry , Aniline Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular StructureABSTRACT
The three-component reaction of dihydropyridines, aldehydes, and p-methylaniline efficiently forms highly substituted tetrahydroquinolines in a stereoselective manner through a Lewis acid-catalyzed formal [4 + 2] cycloaddition. InCl(3) and Sc(OTf)(3) are the catalysts of choice for this process. The in situ generation of a reactive 1,4-dihydropyridine through the regioselective nucleophilic addition of cyanide to pyridinium salts allows a one-pot four-component transformation.
Subject(s)
Dihydropyridines/chemistry , Quinolines/chemical synthesis , Aldehydes/chemistry , Aniline Compounds/chemistry , Cyclization , StereoisomerismABSTRACT
An efficient, modular method for the synthesis of highly substituted tetrahydroquinoline systems is described. The Lewis acid catalyzed interaction of dihydropyridines with glyoxalate and anilines affords the heterocyclic parent systems in good yields. Tandem one-pot processes allow the incorporation of additional components: a preliminary nucleophilic attack on pyridinium salts generates the reactive dihydropyridine in situ, and subsequent electrophilic reactions on the secondary amine complete the assembly of the final targets, which have up to 6 diversity points.
Subject(s)
Dihydropyridines/chemistry , Aldehydes/chemistry , Aniline Compounds/chemistry , Combinatorial Chemistry Techniques , Cyclization , Glyoxylates/chemistry , Molecular StructureABSTRACT
One-electron reduction of pyridinium salts (NAD+ analogues) generates dihydropyridyl radicals which may then be engaged in radical addition processes to regioselectively form gamma-substituted dihydropyridines.
