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[Image: see text] The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound 16 with a 2-methylthiobenzamide. Compound 16 inhibited HDAC3 with an IC(50) of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.

The development of sensitive and chemically selective MRI contrast agents is imperative for the early detection and diagnosis of many diseases. Conventional responsive contrast agents used in 1 H MRI are impaired by the high abundance of protons in the body. 129 Xe hyperCEST NMR/MRI comprises a highly sensitive complement to traditional 1 H MRI because of its ability to report specific chemical environments. To date, the scope of responsive 129 Xe NMR contrast agents lacks breadth in the specific detection of small molecules, which are often important markers of disease. Herein, we report the synthesis and characterization of a rotaxane-based 129 Xe hyperCEST NMR contrast agent that can be turned on in response to H2 O2 , which is upregulated in several disease states. Added H2 O2 was detected by 129 Xe hyperCEST NMR spectroscopy in the low micromolar range, as well as H2 O2 produced by HEK 293T cells activated with tumor necrosis factor.

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.

[Image: see text] The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure–activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

Objectives The primary objective of this study was to evaluate the safety and tolerability of a formulated IL-12 plasmid administered intraperitoneally (IP) in conjunction with intravenous (IV) carboplatin/docetaxel in platinum-sensitive ovarian cancer patients. Methods Escalating doses of IL-12 plasmid (phIL-12) formulated with the lipopolymer PEG-PEI-Cholesterol (PPC) were administered IP every 10–11 days for a total of four treatments and the highest dose was expanded to eight treatments. Patients also received IV carboplatin (AUC 5) and docetaxel (75 mg/m2) every 21 days. Patients were followed for safety, biological activity and antitumor activity after phIL-12/PPC treatment. Results All 13 patients enrolled in the study received both phIL-12/PPC and chemotherapy treatment. There were 49 plasmid-associated adverse events (AEs). The most common AEs were abdominal pain, transient hypotension, low grade fever, catheter site pain, chills, dysgeusia, infusion-related reaction, and nausea. These AEs appeared to be plasmid dose related. Grade 3 AEs included manageable abdominal pain and cytokine release syndrome. There were no dose limiting toxicities and the plasmid treatment did not augment the chemotherapy-associated AEs. The best overall antitumor response (17% CR, 33% PR, 42% SD and 8% PD) was typical of the patient population enrolled for the study. Translational studies showed rise in IFN-γ and TNF-α concentrations in a dose dependent manner. Conclusions The escalating doses and cycles of intraperitoneal phIL-12/PPC when combined with carboplatin/docetaxel chemotherapy in recurrent ovarian cancer patients were well tolerated and did not appear to exacerbate the side effects or attenuate the efficacy of the chemotherapy treatment.

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80–150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor forα -MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

The action of prostaglandin E(2) (PGE(2)) in the preoptic area is thought to play an important role in producing fever. Pharmacologic evidence suggests that, among the four subtypes of E-series prostaglandin (EP) receptors, i.e., EP(1), EP(2), EP(3), and EP(4), the EP(1) receptor mediates fever responses. In contrast, evidence from mice with EP receptor gene deletions indicates that the EP(3) receptor is required for the initial (

Recent studies have identified several neuropeptide systems in the hypothalamus that are critical in the regulation of body weight. The lateral hypothalamic area (LHA) has long been considered essential in regulating food intake and body weight. Two neuropeptides, melanin-concentrating hormone (MCH) and the orexins (ORX), are localized in the LHA and provide diffuse innervation of the neuraxis, including monosynaptic projections to the cerebral cortex and autonomic preganglionic neurons. Therefore, MCH and ORX neurons may regulate both cognitive and autonomic aspects of food intake and body weight regulation. The arcuate nucleus also is critical in the regulation of body weight, because it contains neurons that express leptin receptors, neuropeptide Y (NPY), alpha-melanin-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP). In this study, we examined the relationships of these peptidergic systems by using dual-label immunohistochemistry or in situ hybridization in rat, mouse, and human brains. In the normal rat, mouse, and human brain, ORX and MCH neurons make up segregated populations. In addition, we found that AgRP- and NPY-immunoreactive neurons are present in the medial division of the human arcuate nucleus, whereas alpha-MSH-immunoreactive neurons are found in the lateral arcuate nucleus. In humans, AgRP projections were widespread in the hypothalamus, but they were especially dense in the paraventricular nucleus and the perifornical area. Moreover, in both rat and human, MCH and ORX neurons receive innervation from NPY-, AgRP-, and alpha-MSH-immunoreactive fibers. Projections from populations of leptin-responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight.

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB2 receptor ligands with excellent selectivity over the CB1 receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB2 potency, selectivity and rat exposure.

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.

Tube dilution studies concerned with Thiostrepton were performed on a series of strains of each of the following species of microorganisms: various nonhemolytic streptococci (twelve strains), hemolytic streptococci (ten strains), Staphylococcus aureus (ten strains), Staphylococcus albus (ten strains), and seventeen other selected microorganisms. Tube dilution studies with Thiostrepton against the above-mentioned organisms indicated a marked inhibitory capacity of this antibiotic in extremely low concentration against sensitive microorganisms. The minimum inhibitory concentration of Thiostrepton against the various microorganisms studied after twenty-four hours was as follows: For Staphylococcus aureus, a range of 0.0300 mcg. to 0.0035 mcg. per milliliter, with a median of 0.0150 mcg. per milliliter; for Staphylococcus albus, a range of 0.0625 mcg. to 0.0156 mcg. per milliliter, with a median of 0.0312 mcg. per milliliter; for Streptococcus pyogenes Group A, a range of 0.1250 mcg. to 0.0019 mcg. per milliliter, with a median of 0.0039 to 0.0156 mcg. per milliliter; for nonhemolytic streptococci—Streptococcus faecalis (five strains), a range of 0.5000 mcg. to 0.0078 mcg. per milliliter, with a median of 0.0156 mcg. per milliliter; for Streptococcus mitis (five strains), a range of 0.5000 mcg. to 0.0156 mcg. per milliliter, with a median of 0.0250 mcg. per milliliter; for Streptococcus salivarius (two strains), a range of 1.0000 mcg. per milliliter for one organism and 0.0125 mcg. per milliliter for the other. Eighteen other microorganisms tested, including three E. coli, five A. aerogenes, four salmonella species, four proteus species, one Pseudomonas aeruginosa, and one Mycobacterium phlei were resistant to Thiostrepton in a concentration of one mcg. per milliliter. Five organisms, including one each of pneumococcus Type 1, pneumococcus Type 2, pneumococcus Type 3, Neisseria catarrhalis, and Corynebacterium xerose, were found highly sensitive to Thiostrepton. Further laboratory and clinical studies with Thiostrepton are indicated.