pyrimidinones and Hypersensitivity

For inflammation of a tattoo occurring decades after its creation, sarcoidosis should be considered first of all. Two case of extremely delayed hypersensitivity tattoo reaction have been recently reported in patients treated with BRAF and MEK inhibitors. We report a similar new case strongly suggesting a specific effect of this drug combination.. A 58-year-old man bearing 20-year-old tattoos was treated with dabrafenib and trametinib for advanced melanoma. A painful erythematous swelling appeared on all the patient's tattoos two months later, while his general tolerance of the treatment was poor. Skin biopsy demonstrated perivascular lympho-histiocytic infiltrate without granuloma, but with prominent pigment-loaded macrophages. Inflammatory signs quickly regressed after drug discontinuation.. Great similarity exists between this new case and the first reported case, in which a female patient presented painful infiltration of old tattoos following repeated reintroduction of dabrafenib and trametinib in a setting of advanced melanoma. The immunomodulatory properties BRAF/MEK inhibition may enhance loss of tolerance to tattoo ink, accounting for the extremely long time to reaction. This third case militates in favour of a specific drug-induced reaction, of which patients with tattoos should be informed when anti-BRAF/MEK therapy is being considered.

Topics: Erythema; Humans; Hypersensitivity; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Tattooing

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CXCL12; Disease Models, Animal; Drug Evaluation, Preclinical; Fluorescence Resonance Energy Transfer; Humans; Hypereosinophilic Syndrome; Hypersensitivity; Male; Mice, Inbred BALB C; Models, Molecular; Pyrimidinones; Receptors, CXCR4; Structure-Activity Relationship

The therapeutic potential of transient receptor potential vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized for more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is a major hurdle for the clinical development of these drugs. Here, we describe the properties of 7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (BCTP), a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classic polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC(50) values of 65.4 and 26.4 nM, respectively. Similar activity was observed with rat TRPV1, and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, the inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D(50) value of 2 mg/kg p.o. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through the inhibition of TRPV1. We were surprised to find that BCTP administered orally induced only a maximal 0.6°C increase in core body temperature at the highest tested doses (30 and 100 mg/kg), contrasting markedly with N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide (AMG517), a clinically tested TRPV1 antagonist, which induced marked hyperthermia (>1°C) at doses eliciting submaximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classic polymodal inhibition profile can be identified where the analgesic action is separated from the effects on body temperature.

Topics: Analgesics; Animals; Benzothiazoles; Body Temperature; Body Temperature Regulation; Capsaicin; CHO Cells; Cricetinae; Fever; Humans; Hyperalgesia; Hypersensitivity; Male; Mice; Mice, Inbred C57BL; Pyrimidines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Thiones; Transient Receptor Potential Channels; TRPV Cation Channels

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Topics: Animals; Cells, Cultured; Chromones; Dermatitis, Atopic; Disease Models, Animal; Ear; Edema; Enzyme Inhibitors; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Oxadiazoles; Pyrimidinones; Skin; Tacrolimus; Th1 Cells; Th2 Cells

To determine whether AS-35, a new antiallergic drug, inhibits the activation of eosinophils, we examined the effect of AS-35 on the release of leukotriene C4 (LTC4) and eosinophil peroxidase (EPO) from human eosinophils. Calcium ionophore A23187 caused both LTC4 and EPO release from human eosinophils. AS-35 (1 x 10(-5) M) inhibited A23187-induced LTC4 release from the eosinophils with 56% inhibition. AS-35 (1 x 10(-6) to 1 x 10(-5) M) also inhibited A23187-induced EPO release from the eosinophils in a dose-dependent fashion with 79% inhibition at 1 x 10(-5) M. We concluded that AS-35 prevents the activation of human eosinophils to inhibit LTC4 and EPO release. These results suggest that AS-35 might be useful in controlling allergic diseases by inhibiting eosinophil activation.

Topics: Cells, Cultured; Eosinophil Peroxidase; Eosinophils; Humans; Hypersensitivity; Leukotriene C4; Peroxidases; Pyridines; Pyrimidinones; Tetrazoles

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) on type II to IV allergic reactions and immunological functions were investigated in animal models. Types II to IV allergic reactions in rodents were unaffected in vivo by TBX, even at higher doses than those capable of completely inhibiting the type I allergic reaction. However, both complement-mediated hemolysis via the classical pathway and hypotonic shock-induced hemolysis were slightly inhibited in vitro only by a high concentration of the drug (10(-4) g/ml). In the mouse system, TBX had no ability to suppress anti-hapten IgE antibody formation as well as hemagglutinin formation and to inhibit the proliferation of spleen cells induced by non-specific T and B cell mitogens. The results obtained indicate that TBX is an antiallergic drug essentially devoid of inhibitory actions on types II to IV allergic reactions and immunological functions, thus indicating that it is a specific inhibitor of type I allergic reactions.

Topics: Animals; Arthus Reaction; Cell Division; Complement System Proteins; Erythrocytes; Forssman Antigen; Guinea Pigs; Hemolysis; Histamine Antagonists; Hypersensitivity; Immunity, Cellular; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains; Sheep; Tuberculin Test

A series of 9-hydrazono-4H-pyrido[1,2-a]pyrimidin-4-ones was prepared. The compounds were evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. Structure-activity relationship studies revealed that the presence of a monosubstituted hydrazone moiety in position 9 and an unsubstituted 2-position are necessary for the intravenous activity.

Topics: Animals; Hydrazones; Hypersensitivity; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Structure-Activity Relationship

A new type of antiallergic agent, 9-hydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones, was synthesized and evaluated for inhibitory effects in the rat reagenic passive cutaneous anaphylaxis (PCA) screen. Several racemic 6-methyl derivatives were found to be more potent than disodium chromoglycate intravenously and some were also active orally. Structure-activity relationships are discussed. High stereospecificity was observed in the 6-methyl series between the enantiomers with 6S and 6R absolute configuration, the former being more active. Compound 17, (+)-6(S)-methyl-9-(phenylhydrazono)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid [Chinoin-1045; UCB L140], has an ED50 value of 1.0 mumol/kg po and is now under clinical investigation.

Topics: Animals; Chemical Phenomena; Chemistry; Female; Histamine Release; Hypersensitivity; In Vitro Techniques; Male; Mast Cells; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Topics: Animals; Chemical Phenomena; Chemistry; Hypersensitivity; Male; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

BL-5255, 2-(2-n-propoxyphenyl)-5-(5-1 H-tetrazolyl)pyrimidin-4 (3H)-one, effectively inhibited allergic reactions in sensitized rats or guinea pigs when administered by oral or intravenous routes as the water-soluble sodium or ethanolamine monohydrate salts. In the IgE-mediated rat PCA, BL-5255 was 50 times more potent than disodium cromoglycate by intravenous administration. When administered orally in this model, BL-5255 inhibited the PCA reaction by 50% at 0.1 mg/kg. At less than 0.1 mg/kg p.o., the compound protected conscious actively sensitized guinea pigs from aerosolized antigen-induced collapse. In N. brasiliensis-sensitized rats, BL-5255 administered at 0.1--10 mg/kg p.o. inhibited antigen-induced airway constriction in a dose-related manner. BL-5255 is not a histamine or serotonin antagonist but appears to exert its antiallergic effect by inhibiting the release of mediators.

Topics: Administration, Oral; Airway Obstruction; Animals; Azoles; Dose-Response Relationship, Drug; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; Hypersensitivity, Immediate; Male; Passive Cutaneous Anaphylaxis; Pyrimidinones; Rats; Tetrazoles