ABSTRACT
BACKGROUND: Occlusive treatments are a mainstay in atopic dermatitis (AD) management but may not be well tolerated or lack compliance. A comfortable, semiocclusive, artificial skin barrier that is well tolerated, provides protection, and reduces water loss is needed. OBJECTIVE: To evaluate the potential tolerability and therapeutic benefits of a crosslinked polymer layer (XPL) in adults with AD. METHODS: A single-center, open-label pilot study was conducted involving 10 subjects with moderate to severe AD. Subjects applied XPL up to twice daily for 30 days on a selected treatment area. Investigator's Global Assessment, clinical signs of eczema, and pruritus were assessed on days 1, 3, 5, 15, and 30. Film durability and patient satisfaction were also evaluated. RESULTS: Investigator's Global Assessment scores improved from moderate to severe at baseline to clear to almost clear in 8 of 9 patients at day 30. Pruritus improved from trace to severe itching (baseline) to all subjects having trace to no itching at day 30. There was 1 adverse event of mild exudative dermatitis. LIMITATIONS: The study was limited by small sample size, open-label design, and lack of control. CONCLUSION: XPL may be an effective adjuvant in AD treatment. A larger study with a control group is warranted.
Subject(s)
Dermatitis, Atopic/therapy , Occlusive Dressings , Polymers/administration & dosage , Pruritus/therapy , Administration, Cutaneous , Adult , Cross-Linking Reagents , Dermatitis, Atopic/complications , Dermatitis, Atopic/diagnosis , Female , Humans , Male , Middle Aged , Pilot Projects , Polymers/chemistry , Pruritus/etiology , Severity of Illness Index , Treatment Outcome , Young AdultABSTRACT
This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridones/chemistry , Sulfonamides/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Animals , Binding Sites , Drug Evaluation, Preclinical , Half-Life , Janus Kinase 2/metabolism , Molecular Dynamics Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Pyridones/chemical synthesis , Pyridones/pharmacokinetics , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.
Subject(s)
Aminoimidazole Carboxamide/chemical synthesis , Aminoimidazole Carboxamide/pharmacology , Janus Kinase 2/antagonists & inhibitors , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Aminoimidazole Carboxamide/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Disease Models, Animal , Enzyme Activation/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Microsomes/drug effects , Microsomes/enzymology , Models, Biological , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Thiophenes/chemistryABSTRACT
A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617âPhe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.
Subject(s)
Enzyme Inhibitors/pharmacology , Janus Kinase 2/antagonists & inhibitors , Polycythemia Vera/drug therapy , Animals , Blotting, Western , Cell Proliferation/drug effects , Colony-Forming Units Assay , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Erythropoietin/metabolism , Flow Cytometry , Humans , Mice , Mice, Inbred C57BL , STAT5 Transcription Factor/metabolismABSTRACT
This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.
