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Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.

Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor, representing approximately 15% of all primary CNS malignancies. Historically, the occurrence of GBM is higher in male than in female of reproductive age. Usage of exogenous hormones are known to reduce the risk of glioma development and estrogen improves survival in a glioblastoma animal models, suggesting a potential protective role in GBM. Estrogen receptor β (ERβ) may play a role as a tumor suppressor in GBM, and interestingly its expression decreases in higher-grade tumor samples with loss of differentiation. Therefore, a selective ERβ agonist could be a potential therapy against GBM. OSU-ERb-12 is brain penetrant, orally bioavailable ERβ agonist and demonstrates selectivity of ERβ: ERα = 46:1. In this work, we have tested the efficacy of this drug in vitro against glioma cells and in an orthotopic, syngeneic, immune-intact GBM mouse model. Materials & Methods: We tested the efficacy of OSU-ERb-12, a novel selective ERβ agonist against commercial glioma cell lines and patient derived glioma stem like cells, cell proliferation rate via cell titer Glo assay. To evaluate the cell death Annexin-PI assay was performed using flow cytometry. We also tested impact of this drug on cell cycle distribution using flow cytometry-based assay. For in vivo studies, C57BL/6 mice were intracranially implanted with the murine glioma cell line GL261-Luc2 and treated with 30 mg/kg and 100 mg/kg of OSU-ERb-12. Tumor growth was evaluated post implantation using bioluminescent IVIS imaging and animal survival (Kaplan-Meier) was recorded. Results: Treatment with OSU-ERb-12 significantly reduced the cell proliferation rate of commercial cells and patient derived glioma stem cells from various molecular classifications with IC50= 5 µM, 72h. Cells treated with OSU-ERb-12 showed a time and dose dependent enhancement in programmed cell death. Activation of ERβ did not lead to any significant change in cell cycle pattern. Although treatment with 30 mg/kg OSU-ERb-12 did not show any change in survival (median survival 28 days) of tumor bearing mice, a significantly improved median survival was observed for mice dosed at 100 mg/kg (median survival 45 days) in comparison to vehicle (median survival 28 days). Conclusions: Our study demonstrates an important role of ERβ for glioma cell survival as observed by the potent biological effects of OSU-ERb-12 against glioma cell lines and immune intact murine glioma model that supports the potential for targeting the ERβ as a novel therapeutic strategy for treatment of GBM. Citation Format: Pratibha Sharma, Jayeeta Ghose, Christopher Coss, Chad Bennett, Raju R. Raval, Vinay Puduvalli. Preclinical characterization of OSU- ERb-12, a novel ERβ agonist in Glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1867.

Introduction: The use of allogeneic hematopoietic cell transplantation to treat acute myeloid leukemia (AML) has risen in recent years. However, relapse remains the major cause of mortality post-transplant; while graft-versus-host disease (GVHD) - a T cell mediated immunological disorder is the major cause of non-relapse mortality. Dihydroorotate dehydrogenase (DHODH) supports T cell proliferation by playing a critical role in de novo pyrimidine synthesis and oxidative phosphorylation. We hypothesized that alloreactive T cells may rely on increased levels of pyrimidine pools and ATP to support rapid cell proliferation, making DHODH an interesting target to prevent GVHD. Additionally, DHODH inhibition is currently being pursued as a therapeutic option for AML. Therefore, we hypothesize that DHODH inhibition post-transplant will serve a dual purpose - i) target T cell metabolism to reduce GVHD and ii) prevent relapse due to direct anti-leukemic effects, thereby resulting in superior post-transplant outcomes. Methods: We tested the efficacy of a novel DHODH inhibitor (Cmpd 41), a lead clinical candidate, in preventing GVHD and retaining graft-versus-leukemia (GVL) effect. Human T cells isolated from PBMCs were activated with CD3/CD28 Dynabeads ± Cmpd 41. Cell proliferation (flow cytometry) and ATP production (Agilent Seahorse) was assessed. GVHD and GVL was assessedevaluated in a xenogeneic model where irradiated NSG mice received human PBMCS (~17x106 cells) and treated with vehicle or Cmpd 41 (10mg/kg, 2x/week) with addition of MOLM-13 cells (~1x104) for GVL. Splenocytes were harvested for analysis of cytokine production (intracellular flow cytometry). Results: DHODH inhibition with Cmpd 41 significantly reduced T cell proliferation and ATP production from both glycolysis and OXPHOS (fold change: Cmpd 41 vs. control- 0.56 and 0.68 respectively, p Conclusion: DHODH inhibition is a novel approach to prevent and mitigate GVHD while retaining GVL effects. Combined with direct anti-leukemic effects, we propose that Cmpd 41 treatment in post-transplant relapse in the setting of past or active graft versus host disease will provide dual treatment of AML and GVHD thereby leading to improved patient outcomes. Citation Format: Kara M. Braunreiter, Lotus Neidemire-Colley, Natalie Sell, Yandi Gao, Sandip Vibhute, Chad Bennett, Ola A. Elgamal, Thomas Goodwin, Erin K. Hertlein, John C. Byrd, Parvathi Ranganathan. DHODH inhibition modulates T cell metabolism reducing GVHD and prevents relapse following allogeneic HCT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2335.

Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing of protein phosphatase 2A (PP2A) directly blocks differentiation in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent, OSU-2S, in parallel with genetic approaches, we discovered that PP2A enforced c-Myc and p21 dependent terminal differentiation, proliferation arrest, and apoptosis in AML. Finally, we demonstrated that PP2A activation decreased leukemia-initiating stem cells, increased leukemic blast maturation, and improved overall survival in murine Tet2−/−Flt3ITD/WT and human cell-line derived xenograft AML models in vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.

CD4+ T-cells mediate wound-healing post-myocardial infarction (MI) but exacerbate left-ventricular (LV) remodeling during chronic heart failure (HF). Mechanisms that lead to this transition are unknown. Therefore, we hypothesized that as opposed to MI, T-cells activate specific pathological signals to promote LV-remodeling during chronic HF. To identify such signals, we conducted limited cell RNA-sequencing of CD4+ T-cells sorted from the failing hearts (8 weeks post-MI) of male mice and, surprisingly, found activation of estrogen receptor (ER)-α signaling. As ERα effects are antagonized by ERβ, we tested a novel ERβ agonist (OSU-ERB-012) to modulate T-cell activity and LV remodeling. In-vitro assays showed that OSU-ERB-012 dose dependently inhibit activation and proliferation of T-cells isolated from male mice (IC 50 3.4 μM). In-vivo assays (60 mg/kg/day; oral) showed no overt toxicity and a significant reduction in circulating T cells without affecting neutrophils, monocytes, or B-cells indicating specificity against T-cells. Furthermore, this effect was specific to TCR-mediated T-cell activation and the drug did not affect T-cells stimulated with PMA/Ionomycin suggesting preferential inhibition of antigenically-activated T-cells. To test therapeutic efficacy, male 10-12 week old mice underwent coronary ligation or sham operation and at 4 weeks post-MI randomized according to their cardiac function to receive either the vehicle or OSU-ERB-012 (60 mg/kg/day, oral) for the next 4 weeks. Consistently, at 8 weeks we observed a significant reduction in T-cells in the circulation and the spleens of drug-treated mice when compared with the vehicle treatment. As expected, vehicle treated HF mice showed progressive LV dilatation with significantly increased end-diastolic and end-systolic volumes (EDV and ESV, respectively) from 4-8 weeks post-MI. Importantly, treatment with OSU-ERB-012 significantly inhibited these changes and blunted LV remodeling from 4-8 weeks post-MI. Significant reduction in tibia-normalized heart weights supported these results. Our studies indicate that OSU-ERB-012 is a novel orally-active drug molecule that selectively inhibits T-cell activation and blunts pathological LV-remodeling during chronic HF.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 μM, and Caco-2 data suggested low permeability with active efflux at 2 μM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5–20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUC(last) (26.1 μM*h), and C(max) (0.899 μM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.

This article reveals the formative interplay between the queer art of gossip and poetic practice in James Merrill’s The Changing Light at Sandover, a sprawling verse trilogy composed with the unlikely assistance of a Ouija board. The poem’s extensive gossip with the dead is often dismissed as mere surface. Yet Merrill, the article contends, indulges in what he calls the Ouija’s “backstage gossip” both to establish a queer relationship to poetic tradition and to confront the pervasive menace of the Cold War discourse of the Lavender Scare, which haunts the trilogy’s 1950s origins. Arguing that midcentury American attitudes about sexuality inflect—productively as much as disastrously—the relationship of lyric privacy to gossipy publicity in Merrill’s poem, the article shows how gossip, in its rich afterlife in Sandover, emerges not so much as a normative threat to be overcome but as a mode of fostering and preserving nonnormative voices, converting the privacy imposed on the homosexual into the conditions for creating queer worlds. Gossip concomitantly provides Merrill with a model of poetic self-performance that at once pushes against and embraces New Critical ideals of lyric subjectivity—a way of telling one’s own scandalous story through someone else’s words, even words intended as hostile, discovering poetic and sexual pleasures where others see only anxiety and dread.

Introduction Acute myeloid leukemia (AML) is a disease characterized by the proliferation of undifferentiated myeloid blasts, promoting bone marrow failure, infectious complications, and death. Progress in developing treatments for AML has been slow and clinical outcomes outside of bone marrow transplant are poor. A limitation to progress is the availability of reproducible murine models of AML. As such, there is a critical need to develop new models to quickly screen new therapeutics and treatment combinations. Here we have optimized the engraftment of a spontaneous Idh2R140Q/Flt3ITD murine AML (developed by Shih et al 2017) for rapid in vivo screening of compounds and combination strategies. Methods Spleen derived AML cells from a spontaneous Idh2R140Q/Flt3ITD murine AML were engrafted i.v. into NCG mice. Disease progression was monitored by flow cytometry and LC-MS/MS measurement of plasma D-2-hydroxyglutarate (D2HG), the product of mutant IDH2. At 1 week post-engraftment animals were enrolled onto treatment arms, which included enasidenib (IDH2), gilteritinib (Flt3), a dihydroorotate dehydrogenase (DHODH) inhibitor, and combination arms. In follow-up studies, non-tumor bearing C57Bl/6 mice were treated with various doses of treatment combinations and blood counts, serum liver chemistry, and weight loss were used to evaluate toxicity. Results The time from engraftment to terminal disease can be precisely adjusted to experimental needs, enabling an aggressive 21-day disease course for rapid screening or a more protracted 1.5 month course that limits the initial number of cells required and allows for the testing of slower-acting differentiating agents. We show that enasidenib, gilteritinib, and a DHODH inhibitor all slow disease progression and prolong survival, and that DHODH inhibition may have a greater effect on survival than IDH2 inhibition. We also show that DHODH inhibition lowers plasma D2HG. Importantly, we identify that combining DHODH and IDH2 inhibition is untenable and results in lethal GI toxicity. This was validated in non-tumor bearing mice, where even low doses of DHODH/IDH2 inhibitors in combination resulted in cytopenias and rapid weight loss. Discussion Developing combination treatment regimens is likely to be key to achieving long-term remission for many AML patients; however, efforts to develop these combinations are often stymied by in vitro results that fail to translate to the in vivo setting, particularly unexpected toxicities that are not recognized in vitro. We show that our AML engraftment model can be used to identify and develop pre-clinical compounds and allow us to quickly identify and abandon treatment combinations that are toxic in vivo. Our hope is that this work enables the rapid identification and development of the best novel therapeutics and treatment combinations, such that valuable time and resources can be utilized to their greatest translational effect. Citation Format: Mariah L. Johnson, Ola A. Elgamal, Bonnie Harrington, Allison Mustonen, Amy Lehman, Chad Bennett, Kyle R. Dzwigalski, Kasey L. Hill, Mitch A. Phelps, Jean Truxall, Thomas Goodwin, Alan H. Shih, Ross L. Levine, Erin Hertlein, John C. Byrd. A primary mouse model of AML as a new way to screen novel therapeutics and treatment combinations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6118.

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (−)- 1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer’s disease. Specifically, 4-CF 3 and 4-Br substituted arylsulfone analogs, (−)- 1b and (−)- 1c , are equipotent to compound (−)- 1a . On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.

A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.

Nine species of Uca were collected across the northern Caribbean from 50 locations ranging in habitat osmolality from 18 to 2760 mmol kg−1 (mosmol). The osmoregulating ability of each species was assessed in solutions ranging from 30 to 3550 mosmol. Survivorship, lower and upper median lethal concentration and haemolymph isosmotic concentration ([ISO]) were estimated for each. A lower lethal concentration could not be calculated for some due to survival in low osmolality. By subgenus, average [ISO] for four species from the subgenus Minuca ranged from 587 to 768 mosmol and three species from the subgenus Leptuca from 805 to 881 mosmol. For species from the subgenus Boboruca and the subgenus Uca the [ISO] was 805 and 930 mosmol, respectively. These values reflect the habitat preference of each species in a subgenus. This study broadens our understanding of ecological physiology in Caribbean Uca and demonstrates intra- and inter-specific differences among tropical fiddler crabs.

Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (−) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.

This essay reads Oscar Wilde's Salome and its engagement with the lyric blazon in relation to a range of period representations of Salome. It argues that the blazon--a genre based on the extensive use of decorative language to describe the loved object--provides Wilde with a formal vehicle for negotiating the ethical impasse of poetic ornament and its impossible efforts to embody fully the object of desire. Wilde's text employs the blazon to amplify decorative language's failures even as it cultivates their attendant pleasures, reclaiming as a site of aesthetic and erotic possibility the invisible sphere into which the loved body is cast by the blazon and related modes of poetic embodiment.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

This paper aims to provide the context and model of the development of a new, innovative state-wide service for people with a mental illness and intellectual disability (Dual Disability). Preliminary data on referral patterns and assessments are also discussed

Objective: This paper explores the difficulties the services system in Victoria has in responding to people with intellectual disability (ID) and mental health problems and identifies the underlying assumptions that have led to these. These issues are discussed and where possible put into a Victorian context with the intention of informing service development in the area of Dual Disability (co-morbid mental disorders in people with intellectual disability). Conclusions: People with ID have high levels of mental health need. Generic services have difficulty responding to these needs due to a range of patient, professional and service system factors as well as some of the conceptual issues underpinning policy and legislation.

A short and efficient six-step synthesis of novel phenanthridin-3-one derivatives is described. The synthesis of these derivatives is highlighted by the cyclization of a suitably placed ketone side chain with a thioiminium ion. The derivatives prepared were found to be inhibitors of human steroid 5-α-reductase.

High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

Introduction by the column editor: The period around the onset of the first psychotic episode and the first years after the start of treatment provide pivotal opportunities to affect the course of schizophrenia. Early intervention in schizophrenia is receiving increasing interest, and a number of specialized centers are focusing on treating young people to secure better outcomes and prevent the accrual of disabilities. For example, the Early Psychosis Prevention and Intervention Centre (EPPIC) is a comprehensive treatment service for individuals experiencing their first psychotic episode who live in the western metropolitan region of Melbourne. Readers can learn more at EPPIC's Web site, www.eppic.org.au. About a fifth of persons with recent-onset schizophrenia have persistent psychotic symptoms that translate into disability, suffering, and family burden. Since 1994, a subprogram of EPPIC, the Treatment Resistance Early Assessment Team (TREAT), has been developing a framework for the management of patien...

The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.

A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (CaV3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

Trifluoroacetic acid efficiently catalyzes Prins cyclizations of enol ethers 8 to provide tetrahydropyrans 9 and 10. These tetrahydropyrans are isolated with combined yields of 42-85% and stereoselectivities at C(4) ranging from 95:5 to 50:50 depending on the nature of the substituent R. Unique byproducts of these cyclizations that reveal the presence of underlying equilibria have been isolated and identified. [reaction: see text]

Nine experiments were completed to evaluate the effects of feed manufacturing practices on milling characteristics of diets and growth performance and stomach morphology in pigs. In Exp. 1 and 2, reducing the particle size of sorghum from 800 to 400 [Mu]m improved (P <0.04) efficiency of gain in finishing pigs by 5% but had negative effects on cost of milling and stomach morphology. In Exp. 3 and 4, finishing pigs fed diets with 10 mg/kg of ractopamine HCl, had improved (P <0.05) ADG, G:F, HCW, dressing percentage, and percentage carcass lean. However, increasing mix time of the diet from 0 to 360 s did not affect (P> 0.06) the response of finishing pigs to ractopamine HCl. In Exp. 5 and 6, adding ground and cracked corn to a pelleted supplement for nursery pigs decreased (P <0.01) growth performance compared to feeding a complete pellet. In Exp. 7, increasing the percentage of cracked corn in a diet for finishing pigs decreased development of stomach lesions but also had a generally negative effect on efficiency of gain. In Exp. 8, adding cracked corn to a pelleted supplement (as done for the nursery pigs) decreased milling costs and improved health of stomach tissue. But, G:F was decreased by 6% (P <0.05) which will make this technology unattractive to swine producers. In our final experiment (Exp. 9), pigs fed pellets tended to have the greatest growth performance, pigs fed mash the worst, and pigs fed pellets for only part of the grow-finish phase fell in between. In conclusion, grinding sorghum-based diets for finishing pigs improved efficiency of growth but extensive mixing to maximize diet uniformity had no effect on growth performance or carcass measurements. Use of cracked corn in diets does decrease diet costs and improve stomach health in finishing pigs but feeding of complete pellets for the entire finishing period supports maximum rate and (or) efficiency of gain.

Eleven vinylogous carbonates were examined in the Nussbaumer-Frater variation of the Prins cyclization to provide 2,3,4,6-tetrasubstituted tetrahydropyrans. Results indicate that substrate olefin geometry is a more reliable control element than preset substrate vicinal stereochemistry for establishing C 2 -C 3 vicinal stereochemistry in tetrahydropyran products.