ABSTRACT
Polypeptide antibiotics, such as polymyxins and aminoglycosides, are essential for treatment of life-threatening Gram-negative infections. Acute kidney injury (AKI) attributed to treatment with these agents severely limits their clinical application. Because standard biomarkers (serum creatinine [sCRE] and blood urea nitrogen [BUN]) feature limited sensitivity, the development of novel biomarkers of AKI is important. Here, we compared the performance of standard and emerging biomarkers of AKI for the detection of nephrotoxicity caused by polymyxin B across multiple species (rat, dog and monkey). Further, we applied a biomarker-driven strategy for selection of new kidney-sparing polymyxin analogs. Polymyxin B treatment produced dose-dependent kidney injury observed as proximal tubular degeneration/regeneration and necrosis across all species. Dogs and monkeys had similar biomarker profiles that included increases of both standard (sCRE and BUN) and emerging (urinary neutrophil gelatinase-associated Lipocalin [NGAL] and urinary kidney injury molecule 1 [KIM-1]) biomarkers of AKI. In contrast, only urinary NGAL and urinary KIM-1 were sufficiently capable of detecting kidney injury in rats. Because rats provide a feasible model for screening compounds in drug development, we utilized urinary NGAL as a sensitive biomarker of AKI to screen and rank order compounds in a 2-day toxicity study. To our knowledge, this study provides a first example of successfully applying biomarkers of AKI in drug development.
Subject(s)
Acute Kidney Injury/chemically induced , Acute-Phase Proteins/urine , Anti-Bacterial Agents/toxicity , Lipocalins/urine , Polymyxin B/toxicity , Proto-Oncogene Proteins/urine , Acute Kidney Injury/physiopathology , Animals , Biomarkers/urine , Dogs , Dose-Response Relationship, Drug , Drug Design , Female , Lipocalin-2 , Macaca fascicularis , Male , Rats , Rats, Wistar , Species SpecificityABSTRACT
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Subject(s)
Cross Infection/drug therapy , Drug Discovery , Drug Resistance, Multiple/drug effects , Gram-Negative Bacteria/drug effects , Polymyxins/chemistry , Polymyxins/pharmacology , beta-Alanine/analogs & derivatives , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Dogs , Female , Gram-Negative Bacteria/physiology , Humans , Male , Microbial Sensitivity Tests , Polymyxins/pharmacokinetics , Polymyxins/toxicity , Rats , beta-Alanine/chemistryABSTRACT
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed.
Subject(s)
Piperazines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Dogs , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Models, Molecular , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.
Subject(s)
Biphenyl Compounds/pharmacology , Ether-A-Go-Go Potassium Channels/drug effects , Naphthalenes/pharmacology , Potassium Channel Blockers/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Biphenyl Compounds/chemical synthesis , ERG1 Potassium Channel , Ergolines/pharmacology , Humans , Indicators and Reagents , Mianserin/pharmacology , Naphthalenes/chemical synthesis , Receptor, Serotonin, 5-HT2C/drug effects , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.
