Discovery of potent, selective, and orally bioavailable oxadiazole-based dipeptidyl peptidase IV inhibitors

A novel series of oxadiazole based amides have been shown to be potent DPP-4 inhibitors. The optimized compound 43 exhibited excellent selectivity over a variety of DPP-4 homologs.     

Factor VIIa inhibitors: improved pharmacokinetic parameters

Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.     

Novel 5-azaindole factor VIIa inhibitors

The discovery and development of 5-azaindole factor VIIa inhibitors will be described.     

Scaling of diastolic intraventricular pressure gradients is related to filling time duration

In early diastole, pressure is lower in the apex than in the base of the left ventricle (LV). This early intraventricular pressure difference (IVPD) facilitates LV filling. We assessed how LV diastolic IVPD and intraventricular pressure gradient (IVPG), defined as IVPD divided by length, scale to the heart size and other physiological variables. We studied 10 mice, 10 rats, 5 rabbits, 12 dogs, and 21 humans by echocardiography. Color Doppler M-mode data were postprocessed to reconstruct IVPD and IVPG. Normalized LV filling time was calculated by dividing filling time by RR interval. The relationship between IVPD, IVPG, normalized LV filling time, and LV end-diastolic volume (or mass) as fit to the general scaling equation Y = kM beta, where M is LV heart size parameter, Y is a dependent variable, k is a constant, and beta is the power of the scaling exponent. LV mass varied from 0.049 to 194 g, whereas end-diastolic volume varied from 0.011 to 149 ml. The beta values relating normalized LV filling time with LV mass and end-diastolic volume were 0.091 (SD 0.011) and 0.083 (SD 0.009), respectively (P < 0.0001 vs. 0 for both). The beta values relating IVPD with LV mass and end-diastolic volume were similarly significant at 0.271 (SD 0.039) and 0.243 (SD 0.0361), respectively (P < 0.0001 vs. 0 for both). Finally, beta values relating IVPG with LV mass and end-diastolic volume were -0.118 (SD 0.013) and -0.104 (SD 0.011), respectively (P < 0.0001 vs. 0 for both). As a result, there was an inverse relationship between IVPG and normalized LV filling time (r = -0.65, P < 0.001). We conclude that IVPD decrease, while IVPG increase with decreasing animal size. High IVPG in small mammals may be an adaptive mechanism to short filling times.     

Mechanical forces induced by the transendothelial migration of human neutrophils

The mechanisms regulating neutrophil transmigration of vascular endothelium are not fully elucidated, but involve neutrophil firm attachment and passage through endothelial cell-cell junctions. The goal of this study was to characterize the tangential forces exerted by neutrophils during transendothelial migration at cell-cell junctions using an in vitro laminar shear flow model in which confluent activated endothelium is grown on a microfabricated pillar substrate. The tangential forces are deduced from the measurement of pillar deflection beneath the endothelial cell-cell junction as neutrophils transmigrate. The force diagram displays an initial force increase, which coincides with neutrophil penetration into the intercellular space and formation of a gap in VE-cadherin staining. This is followed by a rapid and large increase of traction forces exerted by endothelial cells on the substrate in response to the transmigration process and the disruption of cell-cell contacts. The average maximum force exerted by an actively transmigrating neutrophil is three times higher than the force generated by an adherent neutrophil that does not transmigrate. Furthermore, we show that substrate rigidity can modify the mechanical forces induced by the transmigration of a neutrophil through the endothelium. Our data suggest that the force induced by neutrophil transmigration plays a key role in the disruption of endothelial adherens junctions.     

Testing Someone Else’s Intelligence: From Regimentation to Freedom1

This article discusses the trend in the development of testing from maximum regimentation of the test-takers’ activity (where they solve problems clearly formulated by the creator with a single correct answer) to diagnostic problematic situations that are very new and indefinite with an open beginning and an open end. With increasing frequency, the open beginning used in testing presupposes a freedom of independent formulation of one’s own research questions of the reality being studied and a search for answers while interacting with that reality. The emergence of mass testing of exploratory behavior is a reflection of the conviction that one of the key abilities that will be required in the very near future is the ability to cope with uncertainty and novelty, including by actively investigating them.

The discussion deals with the problems of testing intelligence and creativity in conditions of novelty and uncertainty, including the “judging problem.” It is pointed out that any thinking test, especially a test of creative thinking, is also an implicit (albeit perhaps not conscious) claim by its developers that their wisdom is virtually unsurpassed. After all, it is assumed that any person’s intelligence and creativity that unfold in a new situation may be described in the context of the model produced by the creative intellect of the test’s developer and, hence, by a more powerful “superintellect.” The errors that are practically inevitable with such an approach can be corrected in a dialog among various groups of researchers or, to the contrary, may be deepened if criticism is shut off.

The article analyzes a fundamental methodological error of creativity testing—the “standard list of creative answers” drawn up by the test-maker in advance, against which the participants’ solutions are checked. This error is explored in the case of an invention-oriented task in the international scholastic test PISA 2012, based on which the education ratings of countries are constructed.

An optimistic thesis is offered: no matter how successful testing is, humankind will never be fully prepared to determine its creative potential, due to its forward development. Without diagnostic tools, however, it will be far less prepared; they are a new and important part of that potential.     

A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic,insulinotropic and anorexigenic activity

Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addition to increasing glucose-dependent insulin secretion, they also cause weight loss. Oxyntomodulin (OXM), a natural peptide with sequence homology to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clinical utility is limited by a short circulatory half-life due to rapid renal clearance and degradation by dipeptidyl peptidase IV (DPP-IV). Here, we describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high molecular weight polyethylene glycol (PEG) (‘PEGylation’). PEG-OXM exerts an anti-hyperglycemic effect in diet-induced obese (DIO) mice in a glucose-dependent manner, with a maximally efficacious dose of 0.1 mg/kg, and reduces food intake and body weight with a minimally efficacious dose of 1 mg/kg. If this pharmacology is recapitulated in patients with type 2 diabetes, these results indicate PEG-OXM as a potential novel once-weekly GLP-1 mimetic with both glucose-lowering activity and weight loss efficacy.     

Synthesis and Anti-HIV Evaluation of 3′-Triazolo Nucleosides

A series of hitherto unknown 3′-α-[1,2,3]-substituted triazolo-2′,3′-dideoxypyrimidine nucleoside analogues of the anti-HIV 3′-azido-3′-deoxythymidine (AZT) were synthesized through catalyzed alkyne-azide 1,3-dipolar cycloaddition (Huisgen reaction). Those 3′-[1,2,3]-triazolo analogues bearing an azido alkyl chain were evaluated for their anti-HIV activity against HIV-1 in primary human lymphocytes as well as for their cytotoxicity in different cells. None of them inhibit HIV replication (EC₅₀ > 20 μM); two of them were converted to their triphosphate form to evaluate their HIV-RT inhibition.     

The LH2 complexes are assembled in the cells of purple sulfur bacterium Ectothiorhodospira haloalkaliphila with inhibition of carotenoid biosynthesis

The effect of the inhibitor of carotenoid (Car) biosynthesis, diphenylamine (DPA), on the cells of the purple sulfur bacterium Ectothiorhodospira (Ect.) haloalkaliphila has been studied. There occurs an inhibition of the biosynthesis of colored Cars (≥99 %) at 71 μM DPA. Considering “empty” Car pockets (Moskalenko and Makhneva 2012) the content of Cars in the DPA-treated samples is first calculated more correctly. The total content of the colored Cars in the sample at 71 μM DPA does not exceed 1 % of the wild type. In the DPA-treated cells (membranes) a complete set of pigment-protein complexes is retained. The LH2 complex at 71 μM DPA is isolated, which is identical to the LH2 complex of the wild type in near IR absorption spectra. This suggests that the principles for assembling this LH2 complex in vivo in the absence of colored Cars remain the same. These results are in full agreement with the data obtained earlier for Allochromatium (Alc.) minutissimum (Moskalenko and Makhneva 2012). They are as follows: (1) DPA almost entirely inhibits the biosynthesis of the colored Cars in Ect. haloalkaliphila cells. (2) In the DPA-treated samples non-colored Cars are detected at 53.25 μM DPA (as traces) and at 71 μM DPA. (3) DPA may affect both phytoene synthase (at ≤71 μM DPA) and phytoene desaturase (at ≥53.25 μM DPA). (4) The assembly of LH2 complex does occur without any colored Cars.