Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.

Prevention of inhalational anthrax after Bacillus anthracis spore exposure requires a prolonged course of antibiotic prophylaxis. In response to the 2001 anthrax attack in the United States, Ϸ10,000 people were offered 60 days of antibiotic prophylaxis to prevent inhalational anthrax, but adherence to this regimen was poor. We sought to determine whether a short course of antibiotic prophylaxis after exposure could protect non-human primates from a high-dose spore challenge if vaccination was combined with antibiotics. Two groups of 10 rhesus macaques were exposed to Ϸ1,600 LD 50 of spores by aerosol. Both groups were given ciprofloxacin by orogastric tube twice daily for 14 days, beginning 1-2 h after exposure. One group also received three doses of the licensed human anthrax vaccine (anthrax vaccine adsorbed) after exposure. In the ciprofloxacin-only group, four of nine monkeys (44%) survived the challenge. In contrast, all 10 monkeys that received 14 days of antibiotic plus anthrax vaccine adsorbed survived (P ‫؍‬ 0.011). Thus postexposure vaccination enhanced the protection afforded by 14 days of antibiotic prophylaxis alone and completely protected animals against inhalational anthrax. These data provide evidence that postexposure vaccination can shorten the duration of antibiotic prophylaxis required to protect against inhalational anthrax and may impact public health management of a bioterrorism event.Bacillus anthracis ͉ treatment ͉ vaccine B acillus anthracis infection in humans occurs as cutaneous, gastrointestinal, or inhalational anthrax depending upon the route of exposure. Cutaneous anthrax is rarely fatal and can be effectively treated with antibiotics. Inhalational anthrax, the form likely to occur after a bioterrorist attack, on the other hand, is difficult to diagnose early, and despite antibiotic therapy, has a high fatality rate. Anthrax is rare in industrialized countries, and vaccination with anthrax vaccine adsorbed (AVA) is confined to those who could be potentially exposed to anthrax, such as veterinary workers, woolen mill employees, and laboratory workers (1). Military personnel in the United States are also vaccinated due to the potential threat of B. anthracis being used as a bioweapon.Past experiments have shown that the rhesus macaque is the animal model that most closely mimics inhalational anthrax in humans (2). In both humans and macaques, inhalational anthrax begins with the deposition of 1-to 5-m spores in the alveolar spaces, where spores are thought to be ingested by alveolar phagocytic cells. Some spores survive inside the phagocyte and are transported to the draining pulmonary and mediastinal lymph nodes where germination occurs. Although most spores probably germinate within a few days after inhalation, germination is not synchronous (3). Some spores remain dormant and do not germinate for prolonged periods (4, 5). It is the delayed germination of retained spores into vegetative bacilli that necessitates the prolonged use of prophylactic antibiotics after an inhalational ...

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The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4'-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans.