Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis.

OBJECTIVE: We have developed a new antihyperglycemic agent (teglicar) through the selective and reversible inhibition of the liver isoform of carnitine palmitoyl-transferase 1 (L-CPT1). RESEARCH DESIGN AND METHODS: Glucose production was investigated in isolated hepatocytes and during pancreatic clamps in healthy rats. Chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats were performed to understand glucose metabolism and insulin sensitivity. RESULTS: In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72 and 50%, respectively. In rats, teglicar reduced the endogenous glucose production (-62%) without affecting peripheral glucose utilization. Heart 2-[(3)H]deoxyglucose uptake in mice was also not affected, confirming in vivo the drug selectivity toward L-CPT1. Chronic treatment in db/db mice (50 mg/kg/bid; 45 days) reduced postabsorptive glycemia (-38%), water consumption (-31%), and fructosamine (-30%). Such antidiabetic activity was associated with an improved insulin sensitivity assessed by the insulin tolerance test. A significant 50% increase in hepatic triglyceride content (HTGC) was found, although plasma alanineaminotransferase was not altered. In addition, long-term teglicar administration to high-fat fed C57BL/6J mice normalized glycemia (-19%) and insulinemia (-53%). Long-term teglicar administration (30 days, 80 mg/kg) in healthy overnight-fasted rats slightly reduced basal glycemia (-20%, ns), reduced basal insulin levels by 60%, doubled triglycerides, and increased free-fatty acids (+53%). HTGC was markedly increased, but liver and peripheral insulin sensitivity assessed by hyperinsulinemiceuglycemic clamp were not affected. CONCLUSIONS: Teglicar, in vitro and in animal models, reduces gluconeogenesis and improves glucose homeostasis, refreshing the interest in selective and reversible L-CPT1 inhibition as a potential antihyperglycemic approach.

SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.

PURPOSE: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. EXPERIMENTAL DESIGN: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo. RESULTS: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. CONCLUSIONS: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.

Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody.

Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor "shedding") followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy.

Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine.

PURPOSE: Acetyl-L-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds. EXPERIMENTAL DESIGN: The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases. RESULTS: ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes. CONCLUSIONS: ALC was effective in enhancing the antitumor potential of platinum compounds in wild-type p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors.

AvidinOX for highly efficient tissue-pretargeted radionuclide therapy.

Avidin is widely used in vitro for its capacity to bind biotin. However, avidin's in vivo use is limited by its short residence in blood and tissues. An avidin variant, named AvidinOX, has been recently described. This product is obtained by 4-hydroxyazobenzene-2'-carboxylic acid-assisted sodium periodate oxidation of avidin. This method generates aldehyde groups from avidin carbohydrates, sparing biotin-binding sites from inactivation. AvidinOX binds cellular and interstitial protein amino groups through Schiff's bases, resulting in a tissue half-life of 2 weeks, compared with 2 hours of native avidin. Binding of AvidinOX occurs in normal and neoplastic tissues. Data show that AvidinOX, administered intranipple in the breast of transgenic BALB/neuT mice, is highly efficient for capturing (90)Y-biotinDOTA, intravenously injected after 48 hours, leading to eradication of multifocal cancer lesions. Efficacy data, together with good tolerability results, indicate that AvidinOX is a highly innovative reagent for tissue-pretargeted radionuclide therapy.

Clinical pharmacokinetics of the new oral camptothecin gimatecan: the inter-patient variability is related to alpha1-acid glycoprotein plasma levels.

AIM OF THE STUDY: To determine the pharmacokinetics of gimatecan, a camptothecin with a lipophilic substitution in position 7, given orally to patients participating in the phase I study. METHODS: Pharmacokinetics was evaluated in 78 patients after oral daily dose for 5 days a week for 1, 2 or 3 weeks by HPLC with a fluorescence detector. RESULTS: Gimatecan was mainly present in plasma as lactone (>85%), the active form as DNA-topoisomerase I poison. The AUC(0-24) on the first day of treatment normalised per daily dose (mg/m(2)), ranged from 194 to 2909 ng h/mL/mg/m(2). The half-life was 77.1+/-29.6h, consequently C(max) and AUC rose 3-6-fold after multiple dosing. Multivariate analysis indicated the daily dose (p<0.0001) and the alpha(1)-acid glycoprotein (AGP) plasma levels (p<0.0001) as main predictors of gimatecan AUC(0-24). In the overall analysis, daily dose and AGP plasma levels explained 85% of the deviance. The hydroxy metabolite ST1698 was present in plasma at low levels with AUC values of 5-15% of gimatecan. In mice, orally treated with gimatecan, plasma and tissue levels were 2-fold higher after treatment with a pro-inflammatory agent causing AGP induction. CONCLUSIONS: Gimatecan is orally absorbed and its variable plasma levels seem to be related to AGP plasma concentrations. Data obtained in mice, together with the fact that AGP levels largely exceeded gimatecan plasma concentrations, suggest that the increased gimatecan levels in patients with high AGP levels are not related to the binding of the drug to AGP with consequent reduced tissue drug distribution, but possibly to other mechanism associated with inflammation being AGP simply a marker of the inflammation process.

Identification of critical residues of the MyD88 death domain involved in the recruitment of downstream kinases.

MyD88 couples the activation of the Toll-like receptors and interleukin-1 receptor superfamily with intracellular signaling pathways. Upon ligand binding, activated receptors recruit MyD88 via its Toll-interleukin-1 receptor domain. MyD88 then allows the recruitment of the interleukin-1 receptor-associated kinases (IRAKs). We performed a site-directed mutagenesis of MyD88 residues, conserved in death domains of the homologous FADD and Pelle proteins, and analyzed the effect of the mutations on MyD88 signaling. Our studies revealed that mutation of residues 52 (MyD88(E52A)) and 58 (MyD88(Y58A)) impaired recruitment of both IRAK1 and IRAK4, whereas mutation of residue 95 (MyD88(K95A)) only affected IRAK4 recruitment. Since all MyD88 mutants were defective in signaling, recruitment of both IRAKs appeared necessary for activation of the pathway. Moreover, overexpression of a green fluorescent protein (GFP)-tagged mini-MyD88 protein (GFP-MyD88-(27-72)), comprising the Glu(52) and Tyr(58) residues, interfered with recruitment of both IRAK1 and IRAK4 by MyD88 and suppressed NF-kappaB activation by the interleukin-1 receptor but not by the MyD88-independent TLR3. GFP-MyD88-(27-72) exerted its effect by titrating IRAK1 and suppressing IRAK1-dependent NF-kappaB activation. These experiments identify novel residues of MyD88 that are crucially involved in the recruitment of IRAK1 and IRAK4 and in downstream propagation of MyD88 signaling.

Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial.

BACKGROUND: Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of the Na+/K+ adenosine triphosphatase and stimulation of sarcoplasmic reticulum calcium adenosine triphosphatase activity. We analyzed data from HORIZON-HF, a randomized, controlled trial evaluating the short-term effects of istaroxime in patients hospitalized with heart failure and left ventricular ejection fraction < or = 35% to test the hypothesis that istaroxime improves diastolic stiffness in acute heart failure syndrome. METHODS: One hundred twenty patients were randomized 3:1 (istaroxime/placebo) to a continuous 6-hour infusion of 1 of 3 doses of istaroxime or placebo. All patients underwent pulmonary artery catheterization and comprehensive 2-dimensional/Doppler and tissue Doppler echocardiography at baseline and at the end of the 6-hour infusion. We quantified diastolic stiffness using pressure-volume analysis and tissue Doppler imaging of the lateral mitral annulus (E'). RESULTS: Baseline characteristics were similar among all groups, with mean age 55 +/- 11 years, 88% men, left ventricular ejection fraction 27% +/- 7%, systolic blood pressure (SBP) 116 +/- 13 mm Hg, and pulmonary capillary wedge pressure (PCWP) 25 +/- 5 mm Hg. Istaroxime administration resulted in an increase in E' velocities, whereas there was a decrease in E' in the placebo group (P = .048 between groups). On pressure-volume analysis, istaroxime decreased end-diastolic elastance (P = .0001). On multivariate analysis, increasing doses of istaroxime increased E' velocity (P = .043) and E-wave deceleration time (P = .001), and decreased E/E' ratio (P = .047), after controlling for age, sex, baseline ejection fraction, change in PCWP, and change in SBP. CONCLUSIONS: Istaroxime decreases PCWP, increases SBP, and decreases diastolic stiffness in patients with acute heart failure syndrome.

OXavidin for tissue targeting biotinylated therapeutics.

Avidin is a glycoprotein from hen egg white that binds biotin with very high affinity. Here we describe OXavidin, a product containing aldehyde groups, obtained by ligand-assisted sugar oxidation of avidin by sodium periodate. OXavidin chemically reacts with cellular and tissue proteins through Schiff's base formation thus residing in tissues for weeks while preserving the biotin binding capacity. The long tissue residence of OXavidin as well as that of OXavidin/biotinylated agent complex occurs in normal and neoplastic tissues and immunohistochemistry shows a strong and homogenous stromal localization. Once localized in tissue/tumor, OXavidin becomes an "artificial receptor" for intravenous injected biotin allowing tumor targeting with biotinylated therapeutics like radioisotopes or toxins. Moreover, present data also suggest that OXavidin might be useful for the homing of biotinylated cells. Overall, OXavidin exhibits a remarkable potential for many different therapeutic applications.

Sympathomimetic inefficiency in restoring contractility in the acute or chronic beta-blocker-treated ischaemic heart: comparison with a new agent.

BACKGROUND: Adequate pharmacologic cardiac support in acute myocardial infarction (MI), as well as in chronic MI patients under beta-blocker therapy, is problematic due to the impaired cardiac response to beta-adrenergic agonists. New therapeutic approaches could resolve this problem. Istaroxime (ISTA) is a new Na(+),K(+)-ATPase inhibitor and SERCA(2) agonist. AIMS: To evaluate: 1) the effects of dobutamine (DOB) on left ventricular function in early (48-72 h) and late (14 days) phases of a post-MI canine model, compared to ISTA, and 2) the efficacy of DOB in chronic left ventricular dysfunction (6 months post-MI) in dogs pre-treated or not with a beta-blocker, compared with ISTA and milrinone (MIL). RESULTS: When compared to the effects in healthy animals, DOB increased contractility only slightly in the first 48-72 h post-MI, whereas its efficacy recovered partially by day 14 and fully by 6 months after MI. ISTA had a greater effect on contractility than DOB and improved relaxation, while DOB did not. Moreover, beta-adrenergic blockade inhibited the inotropic action of DOB, without altering the effect of ISTA. Surprisingly, beta-adrenergic blockade blunted the effects of MIL. CONCLUSION: ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant beta-adrenergic blockade.

Preclinical profile of antitumor activity of a novel hydrophilic camptothecin, ST1968.

ST1968 is a novel hydrophilic camptothecin (CPT) derivative of the 7-oxyiminomethyl series. Because ST1968 retained ability to form remarkably stable cleavable complexes, this study was done to investigate its preclinical profile of antitumor activity in a large panel of human tumor models, including irinotecan-resistant tumors. Although less potent than SN38 in vitro, i.v. administered ST1968 caused a marked tumor inhibition, superior to that of irinotecan, in most tested models. ST1968 exhibited an impressive activity against several tumors including models of ovarian and colon carcinoma in which a high rate of cures was observed. In the most responsive tumors, complete and persistent tumor regressions were achieved even with low suboptimal doses. Even tumors derived from intrinsically resistant cells exhibited a significant responsiveness. Histologic analysis of treated tumors supports a contribution of both proapoptotic and antiangiogenic effects to ST1968 antitumor efficacy. A study done in yeast cells transformed with CPT-resistant mutant forms of topoisomerase I documented that, in contrast to other tested CPT, ST1968 was active against yeasts expressing the mutant K720E enzyme. Based on its outstanding efficacy superior to that of irinotecan and of its good therapeutic index, ST1968 has been selected for clinical development.

Efficacy of a nanocochleate-encapsulated 3,5-diaryl-s-triazole derivative in a murine model of graft-versus-host disease.

We have previously demonstrated that the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole exerts immunosuppressive effects in several experimental models of autoimmunity. These results were achieved by subcutaneously administering ST1959 after dissolution in an oily vehicle, because of its poor water solubility. To circumvent this problem, we sought to determine whether nanocochleate technology could be successfully exploited to deliver ST1959 and protect mice undergoing lethal acute graft-versus-host disease (GVHD). Orally-administered encochleated ST1959 significantly protected animals from lethality, resulting in survival rates of 57% and 100% at doses of 2 and 10 mg/kg, respectively, whereas oral administration of 2 mg/kg ST1959, mixed with empty nanocochleates, was completely inactive. Increased survival was associated with diminished serum chemokine levels and donor CD8+ T cells in the spleen of ST1959-treated mice. Moreover, ST1959 treatment significantly counteracted GVHD-induced normocitic anemia by increasing hemoglobin, hematocrit, platelet, and red and white blood cell counts. Overall, these data show that orally-administered encochleated ST1959 significantly protects mice from GVHD.

Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure.

OBJECTIVES: We examined the hemodynamic, echocardiographic, and neurohormonal effects of intravenous istaroxime in patients hospitalized with heart failure (HF). BACKGROUND: Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase. METHODS: One hundred twenty patients admitted with HF and reduced systolic function were instrumented with a pulmonary artery catheter within 48 h of admission. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 microg/kg/min, the second 1.0 microg/kg/min, and the third 1.5 microg/kg/min istaroxime or placebo. RESULTS: All doses of istaroxime lowered pulmonary capillary wedge pressure (PCWP), the primary end point (mean +/- SD: -3.2 +/- 6.8 mm Hg, -3.3 +/- 5.5 mm Hg, and -4.7 +/- 5.9 mm Hg compared with 0.0 +/- 3.6 mm Hg with placebo; p < 0.05 for all doses). Istaroxime significantly decreased heart rate (HR) and increased systolic blood pressure (SBP). Cardiac index increased and left ventricular end-diastolic volume decreased significantly only with 1.5 microg/kg/min. On echocardiography, left ventricular end diastolic volume and deceleration time improved with 1.5 microg/kg/min. There were no changes in neurohormones, renal function, or troponin I. Adverse events were not life threatening and were dose related. CONCLUSIONS: In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function [HORIZON-HF]; NCT00616161).

Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine), but not the novel atypical antipsychotic ST2472 (9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine), chronic administration induces weight gain, hyperphagia, and metabolic dysregulation in mice.

A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.

Novel substituted aminoalkylguanidines as potential antihyperglycemic and food intake-reducing agents.

We report the synthesis and evaluation of aminoalkylguanidine analogues and derivatives in C57BL/KsJ db/db diabetic mice, following identification by random screening of 1a and 1b as potential antihyperglycemics and/or modulators of food intake. These compounds are related to galegine, a gamma,gamma-dimethylallylguanidine. Between the newly identified compounds, 1h N-(cyclopropylmethyl)- N'-(4-(aminomethyl)cyclohexylmethyl)guanidine showed the most balanced activity as antihyperglycemic and food intake-reducing agent.

Intracellular accumulation and DNA damage persistence as determinants of human squamous cell carcinoma hypersensitivity to the novel camptothecin ST1968.

ST1968, a novel hydrophilic camptothecin analogue of the 7-oxyiminomethyl series, is characterised by the formation of stable DNA-topoisomerase I cleavable complex and by a promising profile of antitumour activity. The present study was designed to extend preclinical evaluation of the novel camptothecin in human squamous cell carcinoma (SCC) models. ST1968 exhibited an impressive activity with a high cure rate in SCC models. ST1968 produced 100% of complete response without evidence of regrowth in tumours characterised by susceptibility to drug-induced apoptosis (FaDu, A431 and A2780). In contrast to irinotecan, ST1968 still showed an excellent, persisting activity in models less susceptible to apoptosis induction (KB, Caski and SiHa), in which drug treatment elicited a persistent DNA damage response, as documented by phosphorylation of p53, RPA-2 and histone H2AX, resulting in delayed apoptosis and senescence. This behaviour was associated with a marked cellular/tumour drug accumulation. In conclusion, ST1968 exhibited an outstanding antitumour activity superior to that of irinotecan against SCC. A high intracellular accumulation, resulting in fast apoptosis or DNA damage persistence, appeared to be a critical determinant of SCC sensitivity to ST1968.

Synthesis and biological activity of fluorinated combretastatin analogues.

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.

Design, synthesis, and in vitro activity of peptidomimetic inhibitors of myeloid differentiation factor 88.

We describe the design and synthesis of a peptidomimetic library derived from the heptapeptide Ac-RDVLPGT-NH 2, belonging to the Toll/IL-1 receptor (TIR) domain of the adaptor protein MyD88 and effective in inhibiting its homodimerization. The ability of the peptidomimetics to inhibit protein-protein interaction was assessed by yeast 2-hybrid assay and further validated in a mammalian cell system by evaluating the inhibition of NF-kappaB activation, a transcription factor downstream of MyD88 signaling pathway that allows production of essential effector molecules for immune and inflammatory responses.

ST2472: a new potential antipsychotic with very low liability to induce side-effects.

ST2472 was shown to bind to multiple receptors, thus resembling the affinity spectrum of atypical antipsychotics. The present study investigates its in-vivo potential antipsychotic effects. ST2472 is effective in the conditioned avoidance response (CAR) test in rats (ED50=1.5 mg/kg p.o.), a model sensitive to antipsychotics. It antagonizes amphetamine-induced hypermotility at dosages (minimal effective dose=0.7 mg/kg p.o.) that are lower than those necessary to antagonize amphetamine-induced stereotypy (minimal effective dose=30 mg/kg p.o.), in rats. This finding, together with the fact that ST2472 does not induce catalepsy in rodents at up to 100 mg/kg p.o., indicates that ST2472 has very low liability to induce extrapyramidal side-effects. ST2472 does not increase prolactinaemia after chronic treatment. In mice, ST2472 does not appear to alter blood pressure and heart rate in a significant fashion. In conclusion, ST2472 seems to be an antipsychotic with lower liability to produce side-effects than other antipsychotics, such as haloperidol, risperidone, olanzapine and clozapine, which were evaluated as reference drugs.