Robert Gerald Linde

Cyclic homopentapeptides 3. Synthetic modifications to the capreomycins and tuberactinomycins: Compounds with activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci

Abstract Modification and replacement of the β-lysine side chain of capreomycin and tuberactinomycin cyclic pentapeptide derivatives resulted in compounds with good antibacterial potency against multidrug-resistant pathogens.

Cyclic homopentapeptides. 1. Analogs of tuberactinomycins and capreomycin with activity against vancomycin-resistant enterococci and Pasteurella

Abstract A 6a-(3′,4′-dichlorophenylamino) analog of viomycin was uncovered by a high-throughput screen against the animal health pathogen Pasteurella haemolytica, and has served as a novel lead structure for our infectious disease programs. We report herein the synthesis and activity of analogs of tuberactinomycins and capreomycin that are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. This paper describes the synthesis and activity of some C-6a-substituted analogs of tuberactinomycins and capreomycin, which are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.

Cyclic homopentapeptides 2. Synthetic modifications of viomycin

Abstract This paper describes synthetic modifications of the C-19 position of tuberactinomycin B (viomycin) and related analogs. The in vitro antibacterial activity of selected analogs against Pasteurella multocida, Escherichia coli and methicillin-resistant Staphylococcus aureus is also discussed. Although C-19 arylation and thiolation did not improve antibacterial activity, C-19 benzyl carbamates, benzyl- and phenyl ureas were found to be more potent than the parent antibiotic.

The identification of orally bioavailable thrombopoietin agonists.

Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

Chapter 17. New Antibacterials for Resistant Organisms

Publisher Summary This chapter focuses on new antibacterials for resistant organisms. The last decade of the 20th century brought with it vancomycin-resistant S. aureus . These glycopeptide intermediate resistant strains (GISA) may receive the most public attention of the resistant bacteria. The chapter focuses on new antibacterial agents reported in the recent past. New parenteral carbapenem, L-786,392, was reported to have excellent gram-positive activity in vitro . The compound was superior to imipenem in vivo , including efficacy in a vancomycin resistant enterococcal (VRE) thigh model. This is believed to be due to lower plasma clearance and the resulting improved pharmacokinetics. The compound has reduced immunotoxicity in monkeys compared to earlier compounds in the series. A comprehensive review of the chemistry, SAR and mechanism of action of quinolones is also discussed. Several late-stage clinical candidates continued to progress through clinical trials. Trovafloxacin and its iv companion, alatrofloxacin, gained US FDA approval and were launched in late January 1998. Recent developments related to glycylcyclines, macrolides, and oxazolidinones are also discussed in the chapter.