NovaBay Pharmaceuticals (United States)

Massively-multitask regression models (MMRMs) have revolutionized activity prediction for drug discovery. MMRMs trained on millions of compounds and many thousands of assays can predict bioactivity with accuracy comparable to 4-concentration IC50 experiments. This report compares six MMRMs: pQSAR, Alchemite, MT-DNN, MetaNN, Macau and IMC. Models were trained by experts in each method, on identical sets of 159 kinase and 4276 diverse ChEMBL assays, employing realistically novel training/test set splits. Results were compared both qualitatively and with statistical rigor. Our use-case is imputing full bioactivity profiles for the very sparse compound collections on which the models were trained. MMRMs performed much better than the single-task random forest regression (ST-RFR) model. Five MMRMs train all models simultaneously, so must leave out test-set measurements from all assays to avoid leakage (here 25% of data), whereas one method trains models one-at-a-time, so only holds out test data for that assay (< 1% of data). Thus, all algorithms were compared both using 75/25 splits, and when possible, 99 + / < 1 splits. Many MMRM evaluations achieved similar accuracy when tested on the same split. However, when evaluated on 75/25 splits, all MMRMs performed much worse than when evaluated on 99 + / < 1% splits. Thus, while many MMRMs produce comparable final production models (trained on all the data), models that require 75/25 splits greatly underestimate the accuracy of the final models. While outstanding for imputations, MMRMs proved little better than ST-RFR for compounds very unlike the training collection. Thus, MMRMs are best for hit-finding, off-target, promiscuity, MoA, polypharmacology or drug-repurposing within the training collection. Since accuracy is not a deciding factor, other pros and cons of each method are also described.

In comparison to modern methods for carbon-SF5 bond formation, methods for direct heteroatom-SF5 bond formation are exceptionally scarce, rendering motifs such as "N-SF5" virtually unexplored in the context of organic and medicinal chemistry. Herein, we demonstrate that direct N-SF5 bond formation can be accomplished through strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes (ABBs), using an easy-to-access solution of SF5Cl. To our surprise, the resultant N-SF5 azetidines proved to be remarkably chemically stable and amenable to peripheral synthetic modifications (e.g., amination, cross-coupling, oxidation, dehalogenation, SN1, and SNAr reactions). The methodology also extends to direct N-SF4CF3 bond formation using trans-CF3SF4Cl, enabling comparative studies throughout this work. From a mechanistic standpoint, DFT calculations, Hammett analyses, and radical trapping experiments support our proposed radical chain propagation mechanism. From a fundamental standpoint, considering N-SF5 and N-SF4CF3 azetidines are heretofore unknown molecular motifs, this work analyzes their dynamic, spectroscopic, and crystallographic features, as well as computed properties (e.g., BDE and pKb values), to provide foundational knowledge and inform downstream applications. While the carbon-bound SF5 group has been employed as a bioisostere for a CF3 group, we posited the N-SF5 motif could be a potential replacement for a small sulfonamide. Accordingly, we synthesized an N-SF5 derivative of a spleen tyrosine kinase inhibitor reported in the patent literature for comparative ADME studies; results from in vitro profiling indicate that an N-SF5 azetidine could indeed be an alternative for an N-SO2Me azetidine, in cases where enhanced lipophilicity is desirable.

Urinary tract infection and blockage are serious and recurrent challenges for people with long-term indwelling catheters, and these catheter problems cause worry and anxiety when they disrupt normal daily activities. The goal was to determine whether urinary catheter-related self-management behaviors focusing on fluid intake would mediate fluid intake-related self-efficacy toward decreasing catheter-associated urinary tract infection (CAUTI) and/or catheter blockage. The sample involved data collected from 180 adult community-living, long-term indwelling urinary catheter users. The authors tested a model of fluid intake self-management related to fluid intake self-efficacy for key outcomes of CAUTI and blockage. To account for the large number of zeros in both outcomes, a zero-inflated negative binomial (ZINB) structural equation model was tested. Structurally, fluid intake self-efficacy was positively associated with fluid intake self-management, suggesting that higher fluid intake self-efficacy predicts more (higher) fluid intake self-management; however, fluid intake self-management was not associated with either the frequency of CAUTIs or the presence or absence of CAUTI. Fluid intake self-efficacy was positively related to fluid intake self-management, and fluid intake self-management predicted less frequency of catheter blockage, but neither fluid intake self-efficacy nor fluid intake self-management predicted the presence or absence of blockage. Further research is needed to better understand determinants of CAUTI in long-term catheter users and factors which might influence or prevent its occurrence. Increased confidence (self-efficacy) and self-management behaviors to promote fluid intake could be of value to long-term urinary catheter users to decrease catheter blockage.

During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent, N-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce N,N-dichlorotaurine (NNDCT). In the present study, 2,2-dimethyltaurine was used to prepare a more stable N-chlorotaurine, namely, N,N-dichloro-2,2-dimethyltaurine (NVC-422). In addition, we report on the chemical characterization, in vitro antimicrobial properties, and cytotoxicity of this compound. NVC-422 was shown effectively to kill all 17 microbial strains tested, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium. The minimum bactericidal concentration of NVC-422 against Gram-negative and Gram-positive bacteria ranged from 0.12 to 4 μg/ml. The minimum fungicidal concentrations against Candida albicans and Candida glabrata were 32 and 16 μg/ml, respectively. NVC-422 has an in vitro cytotoxicity (50% cytotoxicity = 1,440 μg/ml) similar to that of NNDCT. Moreover, our data showed that this agent possesses rapid, pH-dependent antimicrobial activity. At pH 4, NVC-422 completely killed both Escherichia coli and S. aureus within 5 min at a concentration of 32 μg/ml. Finally, the effect of NVC-422 in the treatment of an E. coli-infected granulating wound rat model was evaluated. Treatment of the infected granulating wound with NVC-422 resulted in significant reduction of the bacterial tissue burden and faster wound healing compared to a saline-treated control. These findings suggest that NVC-422 could have potential application as a topical antimicrobial.

ABSTRACT In the wild, it is known that adult female summer flounder, Paralichthys dentatus, grow at a faster rate and to a larger body size than males. The age or size at which this divergence in growth rate occurs is not known. At GreatBay Aquafarms, Inc., the sex ratios of three production lots of juvenile fish was examined to determine if females grow faster than males under commercial cultivation and to identify the age and/or size at which sex-linked growth divergence begins. Production lots 99-2, 99-1, and 98-3, ages 8, 12, and 15 months (post-hatch), respectively, were sampled. The gonadal tissue from fish smaller than 60 mm was examined by histology. Fish larger than 12 cm were dissected, and gross observation was used to determine sex. With the exception of two samples that appeared to be males, gonadal tissue from fish under 60 mm appeared undifferentiated. In production 99-2 (8 months) no significant association between the percentage of female fish and body size was found. However, in productions 99-1 (12 months) and 98-3 (15 months) percentage of female fish increased significantly with body size group. At the time of sampling, the average weight of females from lots 99-2, 99-1, and 98-3 was 1.05, 1.1, and 1.4 times heavier, respectively, than males. Results from this study suggest that sex differentiation in summer flounder occurs at 6 to 12 cm, and indicates clear value of all-female production for the commercial cultivation of summer flounder.

293 The present clinical trial assessed the effects of multiple doses of SDZ RAD, a sirolimus derivative, in stable renal transplant patients. This is a single-center, randomized, double-blind, placebo-controlled study to assess the safety and tolerability of RAD administered once daily for four weeks in stable renal transplant patients. Baseline immunosuppression included Prednisone (5-10 mg) and twice-daily doses of Neoral® individualized to maintain a CsA trough concentration range of 150-300 ng/ml. Adverse events, laboratory parameters, and vital signs were recorded during the 28 day study. Three sequential groups of 8 patients (6 RAD, 2 placebo) received daily doses of either RAD (0.75, 2.5, or 7.5 mg) or placebo in the morning for four weeks. The demographics of the RAD-versus placebo-treated patients were ages 48/43 yrs (range = 25-68 yrs); 50/67% men, and 13/16 vs. 6/6 non-black races. The mean doses of Neoral® or steroid did not change appreciably during the study period. All patients completed the study except one who experienced a serious adverse event (pneumonia) and was replaced by another patient. One patient in the 0.75 mg dose group reported back pain, seizures, and renal carcinoma (unrelated to drug treatment). Three patients in the 7.5mg dose group experienced serious adverse events: pneumonia (dropout), multiple oral herpetic lesions, and left leg pain. At least one mild or moderate adverse event was reported in 4/6 (67%) of RAD patients treated with 0.75 mg, 6/6(100%) patients at 2.5 mg, 4/4 (100%) patients at 7.5mg, and 6/6 (100%) receiving placebo. Although the mean values of cholesterol and triglycerides were elevated at the end point in the 2.5 and 7.5mg RAD dose groups, there were no major differences in group mean leukocyte counts and platelet counts between the placebo and the RAD groups (Table).A four week course of 0.75, 2.5, or 7.5mg/day RAD showed good tolerability and dose-concentration linearity in stable renal transplant recipients. Longer term studies will be needed to assess the effect of RAD on lipid profiles. This research was funded in part by Novatis Pharmaceuticals, East Hanover, NJ

Abstract Sufficient data are available from studies of urethan foams and elastomers to draw semiquantitative conclusions regarding the effect of any gross structural change on most polymer properties. These relationships apply to other areas of application as well, e.g., coatings, adhesives and sealants. Future research may be expected to provide more reliable control of the many reactions involved in preparing urethans, thus better control over structure. Similarly a more quantitative and extensive knowledge of polymer properties may be expected. The result of these combined efforts will be a more precise knowledge of structure-property relationships and an improved ability to produce polymers having the properties desired for a wide range of applications.

Abstract Qualitative and quantitative studies with model compounds have shown that a variety of reactions may occur at 100–300° in molecules containing isocyanate, urea and urethane groups. All or most of these reactions are subject to catalysis so that they may be induced to proceed at lower temperatures. These reactions are quite important as they may affect the production and practical use of polyurethanes and polyureas. By the proper selection of reaction components one may design a polyurethane or polyurea molecule which will give both a reasonable rate of cure to the final state and a degree of temperature stability suitable for many rigorous applications. The choice of reactive groups providing approximately the desired rates of reaction and of suitable catalysts may be used to achieve the necessary curing rate. The initial choice of a catalyst which will have a minimum effect on decomposition reactions, or the removal of the catalyst from the cured polymer will favor polymer stability. A selection of reactants which will minimize those decomposition reactions leading to chain rupture, and which will compensate for what rupture may occur, will promote polymer stability. Simple illustrations of such choices would include eliminating tertiary aliphatic hydroxyl groups from the hydroxyl-bearing component and including some degree of branching commensurate with the degree of elasticity or rigidity desired. Branching should be achieved through the more stable groups, e.g., urethane, urea or trimer, rather than through the less stable allophanate and biuret groups. Many thoroughly tested applications of polyurethanes and mixed polyureaurethanes show that it is readily possible to produce such polymers with excellent thermal stability.