ABSTRACT
One hundred seven 2-arylquinolin-4-amines were assayed in vitro for inhibition of the immunostimulatory effect of oligodeoxynucleotides containing a CpG-motif. The compounds are functionalized with various basic and non-basic groups at the aryl moiety and at the amino substituent of the quinolin-4-amine, and some of them contain an additional substituent at position 6 or 7 of the quinoline. Activities of these antagonists, expressed as EC(50) values, range from 0.2 to 200nM. A statistically significant structure-activity correlation was obtained for the Fujita-Ban variant of the classical Free-Wilson analysis. The CoMFA results derived from several models consistently indicate that electrostatic interactions of the molecules with a biological receptor contribute to biological activities to a greater extent than steric effects.
Subject(s)
Adjuvants, Immunologic/antagonists & inhibitors , Aminoquinolines/pharmacology , Computer Simulation , Lymphoma, B-Cell/drug therapy , Oligodeoxyribonucleotides/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Aminoquinolines/chemistry , Animals , Binding Sites , Cell Line, Tumor , Drug Screening Assays, Antitumor , Mice , Models, Molecular , Molecular Structure , Oligodeoxyribonucleotides/immunology , Oligodeoxyribonucleotides/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Argatroban, a direct thrombin inhibitor used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT), is routinely monitored using the activated partial thromboplastin time (aPTT) yet also prolongs the international normalized ratio (INR). Peritransitional INRs, aPTTs, anticoagulant dosing patterns, and outcomes were evaluated in 165 HIT patients who were transitioned, without guidelines, from argatroban to warfarin therapy. Argatroban (median doses: 1.5-2.0 mcg/kg/min) and warfarin (median dose: 5 mg initially with 3.8 mg/day thereafter) overlapped a median 4 days. Median (5-95th percentile) aPTTs (in seconds) and INRs, respectively, were 59.8 (38.8-82.9) and 3.2 (1.7-7.0) during argatroban monotherapy, 68.6 (44.5-104) and 5.3 (2.4-16) maximally during cotherapy, 59.9 (38.7-92.2) and 4.0 (2.2-11.6) immediately before argatroban cessation during cotherapy, and 36.0 (25.6-60.2) and 2.3 (1.3-7.3) within a median 10-12 hours after argatroban cessation. Major bleeding occurred in 1 (0.6%) patient pretransitionally and no patient during or after cotherapy. Eighteen (10.9%) patients experienced 19 peritransitional adverse outcomes (one death, two amputations, 16 new thromboses); these patients had more severe HIT than event-free patients (median baseline platelet count, 39 vs. 83 x 10(9)/L). Of 108 patients with post-transitional INR data, 43 achieved a therapeutic INR (prospectively defined as 1.9-3.5), 34 were subtherapeutic, and 31 were supratherapeutic, with no across-group trend in new thrombosis. Hence in the absence of guidelines, physicians transfer patients from argatroban to warfarin therapy with acceptably low complication rates in HIT, without systematically over- or under-dosing warfarin. Furthermore, INRs greater than 5 commonly occur in HIT patients during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding.
Subject(s)
Anticoagulants/therapeutic use , Heparin/adverse effects , Pipecolic Acids/therapeutic use , Thrombocytopenia/drug therapy , Warfarin/therapeutic use , Anticoagulants/adverse effects , Arginine/analogs & derivatives , Humans , Infusions, Intravenous , International Normalized Ratio , Partial Thromboplastin Time , Platelet Count , Prospective Studies , Sulfonamides , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
Six dimeric 2-(2-naphthyl)quinolin-4-amines with a linker between the amino groups and eight dimeric 2-(4-anilino)quinolin-4-amines linked between the anilino groups were synthesized and evaluated for their interaction with duplex/triplex DNA's and as antagonists of immunostimulatory oligodeoxynucleotides with a CpG-motif (CpG-ODN). The most powerful triple-helix DNA intercalator known to date, with high affinity toward T.A.T triplets and triplex/duplex selectivity, was found. The potent antagonism of immunostimulatory CpG-ODN by several bis-4-aminoquinolines is not related to their DNA interactions.
Subject(s)
Adjuvants, Immunologic/antagonists & inhibitors , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Intercalating Agents/chemical synthesis , Intercalating Agents/pharmacology , Oligodeoxyribonucleotides/antagonists & inhibitors , Oligonucleotides/antagonists & inhibitors , Adjuvants, Immunologic/pharmacology , DNA/metabolism , Indicators and Reagents , Kinetics , Magnetic Resonance Spectroscopy , Oligodeoxyribonucleotides/pharmacology , Oligonucleotides/pharmacologyABSTRACT
Fifty-seven 2-phenylquinolines substituted at the phenyl group and C4 of the quinoline were synthesized and analyzed for inhibition of the immunostimulatory effect of oligodeoxynucleotides with a CpG-motif. The Fujita-Ban variant of the classical Free-Wilson analysis gave a highly significant correlation for a series of 48 relatively small molecules demonstrating that (i) the partial contributions of substituents to biological activity (EC(50)) are additive and (ii) assuming similar bioavailability for all quinolines studied, the larger molecules cannot be accommodated within a still unknown biological receptor. The results suggest interaction of a basic antagonist molecule with weakly acidic groups in the antagonist-receptor complex. N-[2-(Dimethylamino)ethyl]-2-[4-(4-methylpiperazino)phenyl]quinolin-4-amine (50) is the most effective antagonist found in this study (EC(50) = 0.76 nM).
Subject(s)
Aminoquinolines/chemical synthesis , Immunosuppressive Agents/chemical synthesis , Oligonucleotides/antagonists & inhibitors , Piperazines/chemical synthesis , Quinolines/chemical synthesis , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Animals , CpG Islands , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Mice , Piperazines/chemistry , Piperazines/pharmacology , Quantitative Structure-Activity Relationship , Quinolines/chemistry , Quinolines/pharmacology , Tumor Cells, CulturedSubject(s)
Blood Coagulation Factors/adverse effects , Factor VIII/immunology , Factor VIIa/adverse effects , Hemophilia A/drug therapy , Pulmonary Embolism/chemically induced , Adult , Blood Coagulation Factors/administration & dosage , Blood Coagulation Factors/therapeutic use , Drug Therapy, Combination , Factor VIIa/administration & dosage , Factor VIIa/therapeutic use , Hemophilia A/immunology , Humans , Isoantibodies/immunology , Male , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic useABSTRACT
The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.