ABSTRACT
The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
Subject(s)
Idiopathic Pulmonary Fibrosis/pathology , Integrin alphaV/chemistry , Phenylbutyrates/chemistry , Administration, Oral , Animals , Antigens, Neoplasm/metabolism , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Integrin alphaV/metabolism , Integrin alphaVbeta3/antagonists & inhibitors , Integrin alphaVbeta3/metabolism , Integrins/antagonists & inhibitors , Integrins/metabolism , Molecular Conformation , Molecular Docking Simulation , Phenylbutyrates/pharmacokinetics , Phenylbutyrates/therapeutic use , Protein Structure, Tertiary , Rats , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Structure-Activity RelationshipABSTRACT
A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.
Subject(s)
Betaine/pharmacology , Integrins/antagonists & inhibitors , Pyrrolidines/chemistry , Quaternary Ammonium Compounds/pharmacology , Animals , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Betaine/chemistry , Betaine/pharmacokinetics , Cells, Cultured , Crystallography, X-Ray , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Integrins/chemistry , Integrins/metabolism , Methylation , Models, Chemical , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Conformation , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacokinetics , Rats , StereoisomerismABSTRACT
A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvß1, αvß3, αvß5, αvß6, and αvß8 integrins. Numerous analogs with high affinity and selectivity for the αvß6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvß6 integrin in a radioligand binding assay (p Ki = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
Subject(s)
Drug Discovery , Idiopathic Pulmonary Fibrosis/drug therapy , Integrins/antagonists & inhibitors , Lung/drug effects , Pyrazoles/chemistry , Animals , Antigens, Neoplasm , Cell Adhesion , Dogs , Humans , Lung/metabolism , Male , Mice , Models, Molecular , Molecular Structure , Protein Conformation , Rats , Rats, Wistar , Structure-Activity Relationship , Tissue DistributionABSTRACT
The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, among others. Current inhibitors are designed to mimic the tripeptide sequence (arginine-glycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbß3 have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin therapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic. This review will discuss the discovery of these non-RGD-mimetic inhibitors and the progress that has been made in this promising new chemotype.
Subject(s)
Integrins/antagonists & inhibitors , Molecular Mimicry , Oligopeptides/chemistry , Humans , Integrins/chemistryABSTRACT
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.
Subject(s)
Indoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Picolinic Acids/chemistry , Binding Sites , Crystallography, X-Ray , Indoles/chemical synthesis , Kinetics , Models, Chemical , Molecular Docking Simulation , Phosphodiesterase Inhibitors/chemical synthesis , Picolinic Acids/chemical synthesis , Structure-Activity RelationshipABSTRACT
A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).
Subject(s)
Butyric Acid/chemical synthesis , Butyric Acid/pharmacology , Idiopathic Pulmonary Fibrosis/drug therapy , Integrins/antagonists & inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Antigens, Neoplasm , Butyric Acid/chemistry , Butyric Acid/therapeutic use , Chemistry Techniques, Synthetic , Oxidation-Reduction , Pyrrolidines/chemical synthesis , Pyrrolidines/therapeutic use , StereoisomerismABSTRACT
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
Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.
Subject(s)
Drug Design , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Algorithms , Databases, Factual , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Ligands , Lipids/chemistry , Molecular Structure , SolubilityABSTRACT
Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.
Subject(s)
Drug Design , PermeabilityABSTRACT
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
Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.
