ABSTRACT
Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.
Subject(s)
Fluoroquinolones/chemical synthesis , Fluoroquinolones/pharmacology , Tetracyclines/chemical synthesis , Tetracyclines/pharmacology , Acinetobacter baumannii/drug effects , Microbial Sensitivity Tests , Molecular Structure , Pseudomonas aeruginosa/drug effects , Structure-Activity RelationshipABSTRACT
Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel ß,ß-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.
Subject(s)
Aminoglycosides/chemistry , Aminoglycosides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Neomycin/analogs & derivatives , Aminoglycosides/toxicity , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Cell Line/drug effects , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Drug Resistance, Bacterial/drug effects , Humans , Kidney/cytology , Kidney/drug effects , Microbial Sensitivity Tests , Molecular Structure , RNA/chemistry , RNA/metabolism , Structure-Activity RelationshipABSTRACT
Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.
Subject(s)
Azabicyclo Compounds/pharmacology , Azabicyclo Compounds/pharmacokinetics , Constipation/drug therapy , Drug Discovery , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/pharmacology , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Animals , Azabicyclo Compounds/administration & dosage , Azabicyclo Compounds/therapeutic use , Chronic Disease , Guinea Pigs , Humans , Molecular Structure , Rats , Serotonin 5-HT4 Receptor Agonists/chemistry , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Structure-Activity RelationshipABSTRACT
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.
Subject(s)
Heterocyclic Compounds/chemistry , Piperazines/chemistry , Serotonin 5-HT4 Receptor Agonists/chemistry , Administration, Oral , Animals , Cell Line , Drug Discovery , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/pharmacokinetics , Humans , Male , Molecular Structure , Organ Specificity , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC50 and MIC90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.
ABSTRACT
ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chemistry campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. We tested ACHN-490 against two panels of Gram-negative and Gram-positive pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC(90), ≤4 µg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC(90), 8 µg/ml and 16 µg/ml, respectively). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC(90) of ACHN-490 against AG-resistant staphylococci was 2 µg/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.