ABSTRACT
The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23-induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23-stimulated IL-17A production was observed. In an IL-23-induced rat skin inflammation model, JNJ-77242113 inhibited IL-23-induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23-stimulated IFNγ production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23-driven immune-mediated diseases.
Subject(s)
Interleukin-23 , Receptors, Interleukin , Animals , Humans , Rats , Interleukin-23/metabolism , Administration, Oral , Receptors, Interleukin/metabolism , Male , Signal Transduction/drug effects , Psoriasis/drug therapy , Psoriasis/chemically induced , Colitis/drug therapy , Colitis/chemically induced , Disease Models, Animal , Peptides/pharmacology , Peptides/administration & dosage , Female , Rats, Sprague-DawleyABSTRACT
Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t1/2 < 0.75 h), bioconjugates 35 and 38 have terminal half-lives of â¼2 days in mice and attain significant exposure levels that are maintained up to 7 days. Single dose subcutaneous administration of 35 in lean mice, given 18-20 h prior to oral acetaminophen (AAP) administration, significantly reduced gastric emptying (as determined by plasma AAP levels). In a separate study, similar administration of 35 in fasted lean mice effected a reduction in food intake for up to 48 h. These data are consistent with durable amylinomimetic responses and provide the basis for further development of such long-acting amylinomimetic conjugates for the potential treatment of obesity and associated pathologies.
Subject(s)
Amylin Receptor Agonists , Amylin Receptor Agonists/pharmacology , Amylin Receptor Agonists/therapeutic use , Amyloid , Animals , Body Weight , Humans , Hypoglycemic Agents/therapeutic use , Islet Amyloid Polypeptide/pharmacology , Mice , Obesity/chemically induced , Obesity/drug therapyABSTRACT
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Indazoles/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Indazoles/administration & dosage , Indazoles/chemistry , Ligands , Male , Mice , Mice, Obese , Molecular Structure , Rats , Rats, Sprague-Dawley , Rats, Zucker , Structure-Activity Relationship , ERRalpha Estrogen-Related ReceptorABSTRACT
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.
Subject(s)
Drug Design , Imidazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Pyridines/chemistry , Animals , Binding Sites , Glucose Tolerance Test , Half-Life , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Insulin/metabolism , Molecular Docking Simulation , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphoric Diester Hydrolases/metabolism , Protein Binding , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 µM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.
Subject(s)
Ethers/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Receptors, Estrogen/metabolism , Thiazolidinediones/chemical synthesis , Administration, Oral , Animals , Binding, Competitive , Biological Availability , Crystallography, X-Ray , Diabetes Mellitus/drug therapy , Dogs , Ethers/pharmacokinetics , Ethers/pharmacology , Female , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin Resistance , Ligands , Macaca fascicularis , Male , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Receptors, Estrogen/genetics , Structure-Activity Relationship , Thiazolidinediones/pharmacokinetics , Thiazolidinediones/pharmacology , Triglycerides/blood , ERRalpha Estrogen-Related ReceptorABSTRACT
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
Subject(s)
Macrophages/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Proliferation/drug effects , Fluorescence Polarization , Genes, fos/genetics , Macrophage Colony-Stimulating Factor/metabolism , Mice , Mice, Inbred C57BL , Molecular Structure , Quinolones/pharmacokinetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Spleen/metabolism , Structure-Activity RelationshipABSTRACT
A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.
Subject(s)
Anilides/chemical synthesis , Anilides/pharmacology , Anti-Inflammatory Agents/pharmacology , Piperidines/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Anilides/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Macrophages/drug effects , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors. cFMS exhibits a typical bi-lobal kinase fold, and its activation loop and DFG motif are found to be in the canonical inactive conformation. Both ATP competitive inhibitors are bound in the active site and demonstrate a binding mode similar to that of STI-571 bound to cABL. The DFG motif is prevented from switching into the catalytically competent conformation through interactions with the inhibitors. Activation of cFMS is also inhibited by the juxtamembrane domain, which interacts with residues of the active site and prevents formation of the activated kinase. Together the structures of cFMS provide further insight into the autoinhibition of receptor-tyrosine kinases via their respective juxtamembrane domains; additionally the binding mode of two novel classes of kinase inhibitors will guide the design of novel molecules targeting macrophage-related diseases.
Subject(s)
Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/chemistry , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Amides/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Humans , Molecular Sequence Data , Mutant Chimeric Proteins/antagonists & inhibitors , Mutant Chimeric Proteins/chemistry , Protein Structure, Tertiary/genetics , Proto-Oncogene Mas , Quinolones/chemistry , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, Macrophage Colony-Stimulating Factor/genetics , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Receptor, TIE-2/chemistry , Receptor, TIE-2/genetics , Receptors, Fibroblast Growth Factor/chemistry , Receptors, Fibroblast Growth Factor/geneticsABSTRACT
A series of 2-acylaminothiophene-3-carboxamides has been identified which exhibit potent inhibitory activity against the FLT3 tyrosine kinase. Compound 44 inhibits the isolated enzyme (IC50 = 0.027 microM) and blocks the proliferation of MV4-11 cells (IC50 = 0.41 microM). Structure-activity relationship studies within this series are described in the context of a proposed binding model within the ATP binding site of the enzyme.
Subject(s)
Amides/chemistry , Amides/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Thiophenes/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Binding Sites , Cell Line , Models, Molecular , Molecular Structure , Structure-Activity Relationship , fms-Like Tyrosine Kinase 3/chemistry , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
[reaction: see text] A single-step process for the preparation of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines, 2, was achieved by the reaction of the commercially available 4,6-dichloro-5-aminopyrimidine 1 with isothiocyanates. This mild reaction accommodates a variety of functionalized isothiocyanates and proceeds in good to excellent yields. The utility of such intermediates is exemplified by subsequent reaction with alkyl or arylamine nucleophiles to afford novel, differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines, 3.
Subject(s)
Pyrimidines/chemical synthesis , Thiazoles/chemical synthesis , Molecular Structure , Pyrimidines/chemistry , Thiazoles/chemistryABSTRACT
[reaction: see text] An efficient and versatile method for stereoselective synthesis of (E)-3,3-(diarylmethylene)indolinones by a palladium-catalyzed tandem Heck-carbocyclization/Suzuki-coupling sequence is presented. Factors influencing yield and selectivity, namely catalyst, coordinating ligand, and solvent, are detailed.
ABSTRACT
2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.