ABSTRACT
Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.
Subject(s)
Adamantane/analogs & derivatives , Drug Discovery , Janus Kinase Inhibitors/chemistry , Janus Kinase Inhibitors/pharmacology , Niacinamide/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacokinetics , Adamantane/pharmacology , Adamantane/therapeutic use , Administration, Oral , Animals , Arthritis, Rheumatoid/drug therapy , Biological Availability , Humans , Janus Kinase Inhibitors/pharmacokinetics , Janus Kinase Inhibitors/therapeutic use , Mice , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Niacinamide/pharmacology , Niacinamide/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.
Subject(s)
Gastric Acid/metabolism , H(+)-K(+)-Exchanging ATPase/metabolism , Potassium/metabolism , Proton Pump Inhibitors/pharmacology , Pyrroles/pharmacology , Administration, Oral , Animals , Dose-Response Relationship, Drug , Humans , Male , Molecular Structure , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/chemistry , Pyrroles/administration & dosage , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Subject(s)
H(+)-K(+)-Exchanging ATPase/metabolism , Piperidines/chemistry , Potassium/metabolism , Proton Pump Inhibitors/chemical synthesis , Spiro Compounds/chemistry , Administration, Intravenous , Animals , Area Under Curve , Binding Sites , Drug Evaluation, Preclinical , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , H(+)-K(+)-Exchanging ATPase/chemistry , Half-Life , Histamine/toxicity , Inhibitory Concentration 50 , Molecular Docking Simulation , Naphthalenes/chemistry , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Potassium/chemistry , Proton Pump Inhibitors/chemistry , Proton Pump Inhibitors/pharmacokinetics , ROC Curve , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Subject(s)
Amides/chemistry , Immunologic Factors/chemical synthesis , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Administration, Oral , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Binding Sites , Cell Proliferation/drug effects , Dogs , Graft Rejection/prevention & control , Half-Life , Haplorhini , Humans , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Interleukin-2/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Male , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Pyridines/chemistry , Rats , Rats, Inbred Lew , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Transplantation, HeterotopicABSTRACT
Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Cell Proliferation , Immunomodulation , Lymphocytes/drug effects , Lymphocytes/physiology , Male , Medical Informatics , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Spleen/cytologyABSTRACT
Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Subject(s)
Hedgehog Proteins/metabolism , Lactams/pharmacology , Lactones/pharmacology , Signal Transduction/drug effects , 3T3 Cells , Animals , Drug Discovery , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Lactams/metabolism , Lactones/metabolism , Mice , Patched Receptors , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolismSubject(s)
Gene Expression/genetics , Ligands , Signal Transduction/genetics , Alkaline Phosphatase/biosynthesis , Animals , Binding Sites , Calcineurin , Immunosuppressive Agents , Protein Binding , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction/physiology , T-Lymphocytes/immunology , Tacrolimus/analogs & derivatives , Tacrolimus Binding ProteinsABSTRACT
Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl) or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-N-(arylsulfonyl) 2-enoates is also presented.
