ABSTRACT
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Subject(s)
Amines/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemical synthesis , Ethers/chemical synthesis , Pyrimidines/chemical synthesis , Sulfones/chemical synthesis , Amines/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Chemistry, Pharmaceutical/methods , Cyclooxygenase 2/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Disease Models, Animal , Drug Design , Ethers/pharmacology , Humans , Inflammation , Inhibitory Concentration 50 , Mice , Molecular Structure , Neurodegenerative Diseases/drug therapy , Pyrimidines/pharmacology , Rats , Sulfones/pharmacologyABSTRACT
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.
Subject(s)
Antiviral Agents/pharmacology , Benzodiazepinones/pharmacology , Phenylurea Compounds/pharmacology , Respiratory Syncytial Viruses/drug effects , Amino Acid Sequence , Antiviral Agents/chemical synthesis , Benzodiazepinones/chemical synthesis , Cell Line , Chemical Phenomena , Chemistry, Physical , Cytopathogenic Effect, Viral , Dose-Response Relationship, Drug , Drug Resistance, Viral/genetics , Epithelial Cells/drug effects , Epithelial Cells/virology , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation , Nucleocapsid Proteins/drug effects , Phenylurea Compounds/chemical synthesis , Respiratory Syncytial Viruses/genetics , Tetrazolium Salts , Virus Replication/drug effectsABSTRACT
Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.
Subject(s)
Antiviral Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepinones/chemical synthesis , Phenylurea Compounds/chemical synthesis , Respiratory Syncytial Viruses/drug effects , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Benzodiazepines/pharmacokinetics , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacokinetics , Benzodiazepinones/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Enzyme-Linked Immunosorbent Assay , Humans , In Vitro Techniques , Microsomes/metabolism , Molecular Structure , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Viral Plaque AssayABSTRACT
Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Furans/chemistry , Furans/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Cell Line, Tumor , ErbB Receptors/genetics , ErbB Receptors/metabolism , Furans/chemical synthesis , Humans , Inhibitory Concentration 50 , Lapatinib , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Structure-Activity RelationshipABSTRACT
Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC(50)'s less than 50 muM. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.
