The 8-position side chain of 2-pyridones is believed to be involved in the binding with bacterial DNA gyrase to form the ternary complex, making them very important for the activity of 2-pyridones. A series of 2-pyridones having fluoro-substituted amines at the 8-position has been synthesized and their antibacterial activities and pharmacokinetic properties are reported. (C) 1998 Elsevier Science Ltd. All rights reserved.

Immunosuppressant medications allow the transplantation of tens of thousands of allografts per year and consequently have great potential to decrease patient morbidity and mortality. However, some medications have great risk associated with over- and under-dosing leading to adverse effects or allograft rejection, respectively. This necessitates immunosuppressant therapeutic drug monitoring accomplished by immunoassay or liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). The former's accuracy can be hindered by metabolites of immunosuppressant medications, antibodies against these medications and heterophilic antibodies. Although LC–MS/MS has superior specificity which allows it to be less susceptible to interference, this methodology lacks standardization and the necessary throughput. Recent developments in LC–MS/MS quantitation, however, include patient-friendly sample submission as dried blood spots, higher sample throughput and commercialization. Here we critically review recent LC–MS/MS publications (January 2010 to July 2015) on the quantitation of cyclosporine A, tacrolimus, sirolimus and everolimus.

Background: Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis. Objective: Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis. Methods: Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7. Overall response and signs/symptoms were rated daily on days 1 through 11. Incidence of adverse events and laboratory profile were determined. Results: Mean area under the curve (0.9 to 42.5 ng ·hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed. Comparison to historical intravenous data indicates that absolute bioavailability of topical tacrolimus was less than 0.5%. Ninety-five percent of patients showed at least good improvement. All adverse events were transient. Burning was the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed. Conclusion: The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis. (J Am Acad Dermatol 1998;38:69-76.)

Two practical syntheses of (2S, 4S)-4-tert-butoxycarbonylamino-2-methylpyrrolidine, an important intermediate for quinolone antibacterial agents, have been developed through the combination of diastereo and enantioselective reactions starting from ethyl crotonate and L-alanine, respectively.

Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.