ABSTRACT
An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Isoquinolines/pharmacology , NF-E2-Related Factor 2/antagonists & inhibitors , Phthalimides/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Kelch-Like ECH-Associated Protein 1 , Mice , Models, Molecular , Molecular Structure , Phthalimides/chemical synthesis , Phthalimides/chemistry , Structure-Activity RelationshipABSTRACT
A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure-activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t(1/2)>60 min), minimal CYP inhibition (IC(50)>50 microM) and high cell permeability (Caco-2 P(app) >20x10(-6) cm/s) identified several compounds with drug-like properties.
Subject(s)
Histamine H3 Antagonists/pharmacology , Tetrazoles/pharmacology , Caco-2 Cells , Cell Membrane Permeability , Drug Discovery , Half-Life , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.
Subject(s)
Cross-Linking Reagents/chemistry , Catalysis , Copper/chemistry , Molecular Structure , Palladium/chemistryABSTRACT
Directed metallation and sulfinylation yields sulfoxides which undergo ipso nucleophilic aromatic substitution with tertiary and secondary alkyllithiums, giving aromatic rings bearing alkyl groups generally incompatible with directed metallation methods and with regioselectivity complementary with classical Friedel-Crafts substitution.
Subject(s)
Sulfur/chemistry , Thiocarbamates/chemistry , Benzamides/chemistry , Molecular StructureABSTRACT
Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.
Subject(s)
Amides/chemistry , Models, Chemical , Alkylation , Crystallography, X-Ray , Ephedrine/chemistry , Hydroxylation , Kinetics , Magnetic Resonance Spectroscopy , Molecular Conformation , Oxazoles/chemistry , Proline/chemistry , Stereoisomerism , Sulfur/chemistry , ThermodynamicsABSTRACT
Tertiary 1-naphthamides racemise much more slowly than their laterally lithiated derivatives, and the relative rates of racemisation and epimerisation of these derivatives indicate that the lithium-bearing stereogenic centre inverts via a "conducted tour" mechanism, in which the lithium cation is delivered from one face to the other by coordination to the rotating amide group.