ABSTRACT
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthus Reaction/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Administration, Oral , Aniline Compounds/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Crystallography, X-Ray , Drug Discovery , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Syk KinaseABSTRACT
Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
Subject(s)
Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Catalytic Domain , Cell Line , Computer Simulation , Humans , Indazoles/chemistry , NF-kappa B/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding Sites , Cell Line , Drug Partial Agonism , Humans , Mammary Tumor Virus, Mouse/genetics , Models, Molecular , Molecular Mimicry , NF-kappa B/genetics , Receptors, Glucocorticoid/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoxazines/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Binding, Competitive , Cell Line , Dexamethasone/pharmacology , Humans , Hypersensitivity, Delayed/drug therapy , Mice , Models, Molecular , Radioligand Assay , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/chemistry , Tetrahydronaphthalenes/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Line , Cell Line, Tumor , Humans , Ligands , Mice , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
Subject(s)
Glucocorticoids/agonists , Pyrazoles/chemistry , Receptors, Glucocorticoid/agonists , Amides/chemistry , Binding Sites , Chemistry, Pharmaceutical/methods , Drug Design , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Stereoisomerism , Steroids/chemistryABSTRACT
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.