ABSTRACT
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , Quinolines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Topoisomerase Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , DNA Topoisomerase IV/metabolism , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymology , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/enzymology , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/chemistryABSTRACT
A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Quinolines/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Topoisomerase II Inhibitors , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/metabolism , DNA Topoisomerases, Type II/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Staphylococcus aureus/enzymology , Streptococcus pneumoniae/enzymology , Structure-Activity RelationshipABSTRACT
The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Purinergic P2X Receptor Antagonists/chemical synthesis , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic P2X7/metabolism , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Humans , Molecular Structure , Purinergic P2X Receptor Antagonists/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.
Subject(s)
Benzamides , Drug Discovery , Purinergic P2 Receptor Antagonists , Receptors, Purinergic P2X7/metabolism , Uracil/analogs & derivatives , Administration, Oral , Animals , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacology , Rats , Structure-Activity Relationship , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacokinetics , Uracil/pharmacologyABSTRACT
The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883-94. (c)2010 AACR.
Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/therapeutic use , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Administration, Oral , Animals , Aurora Kinases , Biological Availability , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Histones/metabolism , Humans , Mice , Mice, Nude , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Substrate Specificity/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.
Subject(s)
Receptors, Chemokine/antagonists & inhibitors , Animals , Dogs , Haplorhini , Pharmacokinetics , Receptors, CCR1ABSTRACT
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
Subject(s)
Graft Rejection/prevention & control , Heart Transplantation , Immunosuppressive Agents/pharmacology , Kidney Transplantation , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Animals , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/toxicity , Gene Expression Regulation/drug effects , Graft Survival/drug effects , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/toxicity , Interleukin-2/immunology , Janus Kinase 3 , Lymphocyte Activation/drug effects , Lymphocyte Count , Lymphocyte Culture Test, Mixed , Lymphocyte Subsets/drug effects , Macaca fascicularis , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Myocardium/metabolism , Piperidines , Protein-Tyrosine Kinases/metabolism , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Pyrimidines/toxicity , Pyrroles/administration & dosage , Pyrroles/therapeutic use , Pyrroles/toxicity , Transplantation, Heterotopic , Transplantation, Homologous , Tumor Cells, CulturedABSTRACT
Liver microsomes, and more recently cryopreserved hepatocytes, are commonly used in the in vitro characterization of the metabolism of new xenobiotics. The flavin-containing monooxygenases (FMO) are a major non p450 oxidase present in liver microsomes and hepatocytes. Since FMO is known to be thermally labile, and this enzyme may be involved in the metabolic clearance of some drugs, we sought to more completely characterize the metabolic competency of this enzyme in cryopreserved hepatocytes and in liver microsomes preincubated under various conditions using benzydamine as an in vitro and in vivo probe. The metabolism of benzydamine to its major metabolite, the N-oxide, is mediated by FMO3 in humans. We found that the in vitro microsomal t(1/2) was 70% longer when incubations were prewarmed at 37 degrees C in the absence of NADPH compared with prewarming in the presence of an NADPH-regenerating system, and N-oxide formation was inhibited >99%. Interestingly, the in vivo clearance predicted from these incubations and from human hepatocytes overpredicted the observed clearance of benzydamine in humans (>10.5 versus 2.4 ml/min/kg). In contrast, rat hepatocytes successfully predicted rat in vivo benzydamine clearance to within approximately 30% (>68 versus 48 ml/min/kg). Benzydamine N-oxidation in liver microsomes from all common preclinical species demonstrated heat sensitivity. This information should be considered when extrapolating metabolism data of xenobiotics from these in vitro systems.
