Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.Human respiratory syncytial virus (RSV) is the most important respiratory pathogen that causes lower respiratory tract infections, such as bronchiolitis and pneumonia, in infants and young children, resulting in up to 125,000 hospitalizations annually in the United States (3). The infants most at risk of severe disease are those under 6 weeks of age, those with bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency, and those born prematurely. Hospital admission rates for these groups range between 5% and 30% (20,25). The mortality rate among children admitted to hospital is approximately 3% for those with heart and lung problems and up to 1% for those without these risk factors (11,25). In adults and the elderly, RSV pneumonia is increasingly recognized as a significant cause of morbidity and mortality, being associated with more than 17,000 deaths annually between 1991 and 1998 (9, 22). Among the hospitalized elderly, mortality can be as high as 10 to 20%, and among severely immunocompromised patients with RSV pneumonia, it can be on the order of 50 to 70% (10). There is therefore an urgent and unmet medical need for novel therapies to deal with infections caused by this virus.The development of new therapeutics for RSV was recently reviewed (17,19). Although research into the prevention and treatment of RSV infection has been ongoing for almost 40 years, vaccine development is difficult (8, 13), and to date, there is no clinically approved vaccine. The development of RSV vaccines for use in young infants has been complicated by reduced immune responses in this age group due to immunologic immaturity and the immunosuppressive effects of maternal antibodies. Passive immunization with the monoclonal antibody palivizumab (Synagis) has provided about 50% protection to high-risk children (21). These include infants born prematurely and those with congenital conditions. Because the antibody has to be given prophylactically and treatment is very expensive, its use is limited mainly to developed countries. The effect...

Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a β-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.

OSI-7904L [(S)-2-[5- [(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] is a liposomal formulation of the highly specific, noncompetitive, thymidylate synthase inhibitor OSI-7904 (also known as GW1843, 1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. The studies presented here were conducted to determine the antitumor efficacy, distribution, pharmacokinetics, and safety of OSI-7904L in mice. In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior antitumor efficacy compared with OSI-7904 or 5-fluorouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 although still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904-treated animals. Tumor exposures, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional consistent with saturation of plasma clearance mechanisms. OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration.Thymidylate synthase (TS) catalyzes the synthesis of dTMP by the transfer of a methyl group from 5,10-methylenetetrahydrofolate to the 5-position of the pyrimidine ring of dUMP. Inhibition of TS removes the only source of de novo synthesis of thymine nucleotides and depletes thymine pools (Danenberg et al., 1999) leading to an inhibition of DNA synthesis and eventually cell death. Therefore, TS has been a target of cancer chemotherapy since the advent of 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine over 40 years ago (Heidelberger et al., 1957(Heidelberger et al., , 1958. 5-FU remains a mainstay of treatment for colorectal, breast, and head and neck malignancies. 5-FU is a prodrug that requires conversion to the active fluoropyrimidine nucleotide. Thus, resistance mechanisms can arise through the activation and elimination pathways (for review, see Peters and Köhne, 1999). The objective response rate for 5-FU in colorectal cancer is between 20 and 40% indicating that many patients have or will develop resistance to the drug (Peters and Köhne, 1999). The search for improved TS inhibitors has lately focused upon folate, rather than pyrimidine analogs, in the hope of improving TS selectivity and efficacy.A benzoquinazoline derivative of folate, (...

Prolonging tumor exposure to topoisomerase I inhibitors has been correlated to enhance the efficacy of those agents. Lurtotecan, a water-soluble camptothecin analog, was formulated as a liposomal drug, NX211, to enhance the delivery of drug to tumors. Tumor-bearing mice were treated with either [14C]NX211 containing [14C]lurtotecan, [3H]NX211 containing [3H]phosphatidylcholine or [14C]lurtotecan, euthanized at selected times post-injection, and tissues, plasma, urine and feces were collected. These studies demonstrated that KB tumors of [14C]NX211-treated mice had approximately 70-fold greater concentrations of [14C]lurtotecan at 24 h, respectively, compared to concentrations of [14C]lurtotecan of the KB tumors of [14C]lurtotecan-treated mice. The area under curve (AUC) from 0 to 48 h of [14C]lurtotecan for the KB tumors of [14C]NX211-treated animals was over 17-fold greater than the AUC of [14C]lurtotecan for the tumors of [14C]lurtotecan-treated animals. Treatment with [3H]NX211 demonstrated that the lipid component continually accumulated over 24 h in the tissues. HPLC analysis of extracted material from tumors of [14C]NX211-treated mice showed that more than 95% of the radioactive material was intact [14C]lurtotecan. These findings are one of the keys justifying the development of a liposomal formulation of lurtotecan, which has the intent to increase tumor exposure and increase antitumor efficacy.