ABSTRACT
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
Subject(s)
Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/metabolism , Amino Acid Substitution , Animals , Binding Sites , Binding, Competitive , CHO Cells , Cattle , Cell Line , Chemotaxis/drug effects , Cricetinae , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Kinetics , Models, Molecular , Monocytes/drug effects , Monocytes/physiology , Mutagenesis, Site-Directed , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Radioligand Assay , Receptors, CCR2 , Receptors, Chemokine/chemistry , Receptors, Chemokine/genetics , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Rhodopsin/chemistry , Rhodopsin/genetics , Structural Homology, Protein , TransfectionABSTRACT
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Glycogen Synthase Kinase 3/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridazines/chemical synthesis , Models, Molecular , Pyrazoles/chemistry , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Indicators and Reagents , Isoenzymes/drug effects , Models, Molecular , Structure-Activity RelationshipABSTRACT
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Subject(s)
Enzyme Inhibitors/pharmacology , Phospholipases A/antagonists & inhibitors , Pyrimidinones/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Animals , Cytochrome P-450 CYP2D6 Inhibitors , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Kinetics , Phospholipases A/blood , Phospholipases A2 , Pyrimidinones/chemistry , Rabbits , Recombinant Proteins/antagonists & inhibitorsABSTRACT
A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.
Subject(s)
Phenols/pharmacokinetics , Pyrrolidines/pharmacokinetics , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Animals , Blood-Brain Barrier , Heterocyclic Compounds , Indoles , Phenols/chemical synthesis , Phenols/pharmacology , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacokineticsABSTRACT
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.
Subject(s)
Biphenyl Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Lipoproteins/metabolism , Phospholipases A/antagonists & inhibitors , Pyrimidinones/pharmacology , Administration, Oral , Animals , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/chemistry , Biphenyl Compounds/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Phospholipases A/metabolism , Pyrimidinones/administration & dosage , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Rabbits , Structure-Activity RelationshipABSTRACT
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.
