ABSTRACT
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
Subject(s)
Cyclopropanes/pharmacology , Drug Discovery , Oxazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , TYK2 Kinase/antagonists & inhibitors , Animals , Catalysis , Crystallography, X-Ray , Cyclopropanes/chemistry , Humans , Mice , Oxazoles/chemistry , Protein Binding , Protein Kinase Inhibitors/chemistry , Psoriasis/drug therapy , Structure-Activity Relationship , TYK2 Kinase/metabolismABSTRACT
Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.
Subject(s)
Drug Design , Fingolimod Hydrochloride/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Receptors, Lysosphingolipid/agonists , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Dogs , Dose-Response Relationship, Drug , Fingolimod Hydrochloride/administration & dosage , Fingolimod Hydrochloride/chemistry , Freund's Adjuvant/administration & dosage , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/chemistry , Ligands , Lymphocytes/drug effects , Macaca fascicularis , Male , Mice , Molecular Structure , Mycobacterium/drug effects , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Tissue DistributionABSTRACT
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Animals , Carbazoles/pharmacokinetics , Crystallography, X-Ray , Female , Humans , Isomerism , Macaca fascicularis , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/metabolism , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Subject(s)
Arthritis, Experimental/drug therapy , Lysophospholipids/agonists , Sphingosine/analogs & derivatives , Structure-Activity Relationship , Administration, Oral , Animals , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Lymphocyte Count , Male , Rats, Inbred Lew , Receptors, Lysosphingolipid/agonists , Sphingosine/agonistsABSTRACT
Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
Subject(s)
Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Lysophospholipids/agonists , Sphingosine/analogs & derivatives , Animals , Arthritis, Experimental/drug therapy , CHO Cells , Cell Movement/drug effects , Cell Proliferation/drug effects , Cricetinae , Cricetulus , Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Humans , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Lymphatic System/cytology , Lymphatic System/drug effects , Lymphocytes/drug effects , Mice , Mice, Inbred C57BL , Rats , Rats, Inbred Lew , Sphingosine/agonists , Structure-Activity Relationship , Thymus Gland/cytology , Thymus Gland/drug effectsABSTRACT
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.
Subject(s)
Acetamides/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , I-kappa B Kinase/antagonists & inhibitors , Acetamides/chemical synthesis , Acetamides/pharmacology , Administration, Oral , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inflammatory Bowel Diseases/drug therapy , Inhibitory Concentration 50 , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.
Subject(s)
Amides/chemistry , Arachidonate 15-Lipoxygenase/chemistry , Lipoxygenase Inhibitors/chemistry , Pyrazoles/chemistry , Amides/chemical synthesis , Amides/pharmacology , Animals , Arachidonate 15-Lipoxygenase/metabolism , CHO Cells , Cricetinae , Cricetulus , Humans , Hydroxyeicosatetraenoic Acids/blood , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Subject(s)
Arthritis, Rheumatoid/drug therapy , I-kappa B Kinase/antagonists & inhibitors , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Thiazoles/chemistry , Animals , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Female , I-kappa B Kinase/metabolism , Mice , Mice, Inbred BALB C , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure-activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Animals , I-kappa B Kinase/metabolism , Imidazoles/chemistry , Imidazoles/pharmacology , Lipopolysaccharides/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , I-kappa B Kinase/antagonists & inhibitors , Imidazoles/chemical synthesis , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Animals , Crystallography, X-Ray , Female , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , I-kappa B Kinase/genetics , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
Subject(s)
Imidazoles/pharmacology , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Imidazoles/chemistry , Lipoxygenase Inhibitors/chemistry , Male , Rats , Rats, Sprague-DawleyABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
