The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.

Background & Aims : Sofosbuvir is a potent hepatitis C NS5B polymerase inhibitor that has led to high-sustained viral response rates when combined with other direct-acting antivirals. To date, no data exists on the combination of sofosbuvir with the NS3 protease inhibitor, telaprevir. The safety, tolerability, and efficacy of an all-oral 12-week regimen of telaprevir in combination with sofosbuvir were evaluated in this open-label, phase 2 study. Methods: Twenty adults with genotype 1 hepatitis C infection who were non-cirrhotic and naive to therapy received telaprevir 1125 mg orally twice-daily plus sofosbuvir 400 mg once daily for 12 weeks. Results : Telaprevir plus sofosbuvir was generally well tolerated, with all 20 subjects completing treatment. The five most common adverse events were nausea, rash, headache, ano-rectal symptoms, and pruritus. Two subjects required discontinuation of telaprevir after week 4 but were maintained on sofosbuvir till the end of treatment. Sustained virologic response 12 weeks after the end of treatment was 95%. Conclusion : The results provide valuable information regarding the safety, tolerability and efficacy of telaprevir combined with sofosbuvir as dual therapy in naive non-cirrhotic genotype 1 patients.

The natural compound curcumin has been investigated as an anticancer agent in many cellular systems, in animal models and in the clinic. The overriding negative characteristics of curcumin are its low solubility, weak potency and poor bioavailability. We have examined the efficacy and mechanism of action of a synthetic curcumin analog, UBS109, in head and neck squamous cell carcinoma. By nephelometry, this analog exhibits considerably greater solubility than curcumin. Pharmacokinetic studies of a single oral dose of UBS109 in mice revealed that peak plasma concentrations were reached at 0.5 hours post-dose (Tmax) with average plasma concentrations (Cmax) of 131 and 248 ng/mL for oral doses of 50 and 150 mg/kg, respectively. The terminal elimination half-lives (T½) for these doses averaged 3.7 and 4.5 hours, respectively. In both in vitro and in vivo studies, we found that UBS109 decreased the levels of phosphorylated IKKβ and phosphorylated p65 and, unexpectedly, increased the levels of phosphorylated IκBα by Western blot analysis. These observations may suggest that UBS109 suppresses tumor growth through, in part, inhibition of NF-κB p65 phosphorylation by PKAc and not through IκBα. Finally, we demonstrate that UBS109 is efficacious in retarding the growth of Tu212 (head and neck) squamous cell carcinoma (SCC) xenograft tumors in mice and may be useful for treating head and neck SCC tumors.

Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013330 FLUORINATION OF ENIGMOL IMPROVES TISSUE UPTAKE AND AFFECTS IN VIVOPROSTATE CANCER EFFICACY Suzanne G. Mays, Mark T. Baillie, Eric J. Miller, Anatoliy S. Bushnev, Sarah T. Pruett, Deborah G. Culver, Taylor J. Evers, Jingjing Gao, G. Prakabahr Reddy, Michael G. Natchus, Richard F. Arrendale, Randy B. Howard, Dennis C. Liotta, and John A. Petros Suzanne G. MaysSuzanne G. Mays Atlanta, GA More articles by this author , Mark T. BaillieMark T. Baillie Atlanta, GA More articles by this author , Eric J. MillerEric J. Miller Atlanta, GA More articles by this author , Anatoliy S. BushnevAnatoliy S. Bushnev Atlanta, GA More articles by this author , Sarah T. PruettSarah T. Pruett Atlanta, GA More articles by this author , Deborah G. CulverDeborah G. Culver Atlanta, GA More articles by this author , Taylor J. EversTaylor J. Evers Atlanta, GA More articles by this author , Jingjing GaoJingjing Gao Atlanta, GA More articles by this author , G. Prakabahr ReddyG. Prakabahr Reddy Atlanta, GA More articles by this author , Michael G. NatchusMichael G. Natchus Atlanta, GA More articles by this author , Richard F. ArrendaleRichard F. Arrendale Atlanta, GA More articles by this author , Randy B. HowardRandy B. Howard Atlanta, GA More articles by this author , Dennis C. LiottaDennis C. Liotta Atlanta, GA More articles by this author , and John A. PetrosJohn A. Petros Atlanta, GA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1715AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous preclinical studies have established that the novel sphingosine analog, Enigmol ([2S,3S,5S]-2-amino-3,5-dihydroxyoctadecane), inhibits growth of prostate tumors. Fluorination of Enigmol was hypothesized to improve uptake by increasing drug hydrophobicity, which could lead to greater efficacy. The objectives of these studies were to investigate pharmacokinetics and in vivoefficacy of two fluorinated Enigmol analogs, called analogs A and B(structures to be revealed at the meeting). METHODS PK studies used male Sprague-Dawley rats (n=4) given a single oral dose of Enigmol or analog (10 mg/kg). Two xenograft studies were conducted, each of which compared a fluorinated analog to Enigmol. Nude mice with established subcutaneous PC3 xenografts were gavaged daily with vehicle, Enigmol, or either A (exp. 1) or B (exp. 2), (10 mg/kg; n=10-11). Tumor sizes and body weights were monitored over time. Significance of differences in tumor growth was assessed by linear mixed model for repeated measurements: p<0.05 was considered significant. Drug levels in plasma, several normal tissues (PK), and tumor tissues (exp. 2) were quantified by mass spectrometry. RESULTS Both fluorinated analogs reached higher plasma concentrations than Enigmol (A, 40+/− 11 ng/ml; B, 67 +/− 6; Enigmol, 25+/− 2 ng/ml) and accumulated at higher levels than Enigmol in all normal tissues examined (for example, in prostate: A, 23+/− 9; B, 12 +/− 4; Enigmol, 0.27 +/− 0.08 μg/g after 24 hours). A caused statistically significantly slower tumor growth rates than vehicle or Enigmol (p=0.0002 vs vehicle; p=0.04 vs Enigmol, Fig. 1). In the second xenograft study, Enigmol slowed tumor growth rate compared to controls (p=0.02), but B did not (p=0.17), although tumor drug levels at the end of the study were ∼5-fold higher than in the Enigmol group. Mice treated with B lost weight (12%), suggesting host toxicity. Weight loss was not seen with any other groups in these studies. CONCLUSIONS Fluorination of Enigmol improved uptake and tissue distribution as hypothesized. The two fluorinated analogs had differing effects on tumor growth rates of PC3 xenografts: B was less effective than Enigmol, while A was superior. The increased efficacy and apparent lack of toxicity of A are notable and suggest that this analog has therapeutic potential. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e133-e134 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Suzanne G. Mays Atlanta, GA More articles by this author Mark T. Baillie Atlanta, GA More articles by this author Eric J. Miller Atlanta, GA More articles by this author Anatoliy S. Bushnev Atlanta, GA More articles by this author Sarah T. Pruett Atlanta, GA More articles by this author Deborah G. Culver Atlanta, GA More articles by this author Taylor J. Evers Atlanta, GA More articles by this author Jingjing Gao Atlanta, GA More articles by this author G. Prakabahr Reddy Atlanta, GA More articles by this author Michael G. Natchus Atlanta, GA More articles by this author Richard F. Arrendale Atlanta, GA More articles by this author Randy B. Howard Atlanta, GA More articles by this author Dennis C. Liotta Atlanta, GA More articles by this author John A. Petros Atlanta, GA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.

The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC(50) = 60 nM) with an aqueous solubility of approximately 60 μg/mL. The agent shows a 10-fold exposure (AUC/C(max)) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg, and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.

After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity.

Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.

A new compound, [Cd(mipit)4][PF6]2 has been synthesized and characterized via standard solid and solution state methods including single crystal X-ray crystallography (mipit = 1-methyl-3-(2-propyl)-2(3H)-imidazolethione). The title compound crystallizes in tetragonal space group I4 1 /a with a = 12.478(2) Å, b = 12.478(2) Å, c = 28.806(6) Å, and Z = 4. The complex is a high melting, colorless solid that has a distorted tetrahedral CdS4 coordination geometry. Thermogravimetric analysis results for the title compound as well as for another potential CdS synthon and two potential CdSe synthons are reported.