ABSTRACT
Highly TRß selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRß) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRß selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRß specificity in a binding assay and exhibited full agonism in a reporter cell assay.
Subject(s)
Drug Design , Malonates/pharmacology , Thyroid Hormone Receptors beta/agonists , Dose-Response Relationship, Drug , Humans , Malonates/chemical synthesis , Malonates/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).
Subject(s)
Glucosides/chemistry , Hypoglycemic Agents/chemical synthesis , Sodium-Glucose Transporter 1/antagonists & inhibitors , Animals , Blood Glucose/analysis , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Glucosides/chemical synthesis , Glucosides/therapeutic use , Humans , Hyperglycemia/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Molecular Conformation , Rats , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2 Inhibitors , Structure-Activity RelationshipABSTRACT
Thyromimetics that specifically target TRß have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRß) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRß selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.
Subject(s)
Dyslipidemias/metabolism , Indans/chemistry , Liver/metabolism , Molecular Mimicry , Thyroid Hormone Receptors beta/agonists , Animals , Arginine/chemistry , Cholesterol/administration & dosage , Cholesterol/metabolism , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Dyslipidemias/drug therapy , Humans , Ligands , Liver/drug effects , Male , Malonates/chemical synthesis , Malonates/chemistry , Models, Molecular , Molecular Structure , Rats , Rats, Wistar , Small Molecule Libraries , Structure-Activity Relationship , Thyroid Hormone Receptors beta/metabolismABSTRACT
Zeta-associated protein, 70 kDa (ZAP-70), a spleen tyrosine kinase (Syk) family kinase, is normally expressed on T cells and natural killer cells and plays a crucial role in activation of the T cell immunoresponse. Thus, selective ZAP-70 inhibitors might be useful not only for treating autoimmune diseases, but also for suppressing organ transplant rejection. In our recent study on the synthesis of Syk family kinase inhibitors, we discovered that novel imidazo[1,2-c]pyrimidine-8-carboxamide derivatives possessed potent ZAP-70 inhibitory activity with good selectivity for ZAP-70 over other kinases. In particular, compound 26 showed excellent ZAP-70 kinase inhibition and high selectivity for ZAP-70 over structurally related Syk. The discovery of a potent, highly selective ZAP-70 inhibitor would contribute a new therapeutic tool for autoimmune diseases and organ transplant medication.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , ZAP-70 Protein-Tyrosine Kinase/antagonists & inhibitors , Amides , Benzene Derivatives , Humans , Immunity , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , ZAP-70 Protein-Tyrosine Kinase/immunologyABSTRACT
Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70k Da (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3-c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5-c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2-c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model.
Subject(s)
Imidazoles/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Crystallography, X-Ray , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins/classification , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/classification , Protein-Tyrosine Kinases/metabolism , Pyrimidines/chemistry , Structure-Activity Relationship , Syk Kinase , ZAP-70 Protein-Tyrosine Kinase/antagonists & inhibitors , ZAP-70 Protein-Tyrosine Kinase/metabolismABSTRACT
A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.
Subject(s)
Amidines/chemical synthesis , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Factor Xa Inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Administration, Oral , Amidines/pharmacology , Animals , Biological Availability , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Mice , Models, Chemical , Molecular Structure , Oximes/chemistry , Prodrugs/chemistry , Trypsin/chemistryABSTRACT
Splenic tyrosine kinase (Syk) family kinases, which are members of the protein tyrosine kinase family, play crucial roles in immune responses, with Syk participating in B-cell activation and the zeta-associated protein 70 kDa (ZAP-70) kinase being involved in T-cell activation. Therefore, Syk family kinase inhibitors are candidate therapeutic agents for the treatment of various allergic disorders and autoimmune diseases. We designed 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives as Syk family kinase inhibitors, based on literature reports and structure-based drug design. These derivatives showed significant Syk inhibitory activities, with ZAP-70 inhibition. Representative compounds 10d and 11 not only exhibited strong inhibition of both Syk and ZAP-70 kinase but also suppressed IL-2 production by peripheral blood mononuclear cells and whole blood.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Binding Sites , Drug Design , Humans , Interleukin-1/metabolism , Leukocytes/drug effects , Leukocytes/metabolism , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Syk KinaseABSTRACT
We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f.HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.
