Nonpeptide angiotensin II antagonists derived from 1H-pyrazole-5-carboxylates and 4-aryl-1H-imidazole-5-carboxylates

Two series of potential angiotensin II antagonists derived from carboxyl-functionalized "diazole" heterocycles have been prepared and evaluated. Initially, a limited investigation of 4-arylimidazole-5-carboxylates led to 2-n-butyl-4-(2-chlorophenyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-y l] methyl]-1H-imidazole-5-carboxylic acid (12b), which was found to be a highly potent antagonist of the rabbit aorta AT1 receptor (IC50 0.55 nM). In conscious, normotensive rats, 12b at 0.1 mg/kg iv inhibited the pressor response to AII by 88%, with a duration of > 6 h. More extensively studied was an isosteric series of 3-alkyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazole -5- carboxylates bearing aryl, alkyl, or aralkyl substituents at N1. These compounds were available in highly regioselective fashion via condensation of a substituted hydrazine hydrochloride with a 2-(methoxyimino)-4-oxoalkanoate intermediate. In vitro, the most potent pyrazolecarboxylic acids had n-butyl at C3 and were substituted at N1 by such groups as 2,6-dichlorophenyl (19h), 2-(trifluoromethyl)phenyl (19k), benzyl (19t), and phenethyl (19u), all with IC50 values of 0.18-0.24 nM. Although less potent in the receptor assay, 3-n-propylpyrazolecarboxylic acids were at least as effective as their butyl counterparts in vivo. Several of the pyrazolecarboxylic acid derivatives demonstrated potent, long-lasting oral activity in rats. At 1 mg/kg po, the 1-benzyl-3-butyl (19t), 1-(2,6-dichlorophenyl)-3-propyl (19v), 3-propyl-1-(2,2,2-trifluoroethyl) (19y), and 1-benzyl-3-propyl (19z) analogues all gave > or = 75% inhibition of the AII pressor response in the rat model, with duration of action > 23 h.     

Determination of the amino end groups in polyamide 6 and 6,6 with ninhydrin

The amino end groups in polyamide 6 and 6,6 were reacted in a water/methylcellosolve/propionic acid/sodium propionate/pyridine/isopropanol system for 30 min at 100°C with ninhydrin to give a dye (λ_max : 570 nm, ?₅₇₀ : 18.6 · 10³ cm² mol^?1), whose photometrically determinable concentration represented a measure of the amino end group content. Although the polymer remained undissolved during the analysis, the reaction proceeded quantitatively in all the samples studied (fibres with a maximum fineness of 44 dtex, corresponding to a diameter of 70 μm). ?-Aminocaproic acid served as a low-molecular calibration substance for the polymer. On account of its simplicity, rapidity, and good reproducibility (variation coefficient 3.4%), the ninhydrin method is suitable for the serial determination of the amino end groups in polyamide 6 and 6,6.     

Reversible addition fragmentation chain transfer polymerization of 3-[tris(trimethylsilyloxy) silyl] propyl methacrylate

Reversible addition fragmentation chain transfer (RAFT) bulk polymerizations of 3-[tris(trimethylsilyloxy)silyl] propyl methacrylate (TRIS) have been carried out at 60 °C, employing cumyl dithiobenzoate (CDB) and 2-cyanoprop-2-yl dithiobenzoate (CPDB) as mediating agents at concentrations ranging from 5.0×10⁻³ to 2.0×10⁻² mol l⁻¹. The monomer conversion vs. time evolution was followed via dilatometry and ¹H NMR spectroscopy. The CDB mediated polymerization displays RAFT agent concentration dependent inhibition and rate retardation phenomena, whereas the CPDB mediated polymerization process is less susceptible to rate retardation and inhibition effects. The different behavior of CDB and CPDB in TRIS polymerization is most likely due to the increased stability of the intermediate macroRAFT radicals in the CDB mediated process. The generated RAFT polymers were analyzed via size exclusion chromatography indicating linear macromolecular growth with respect to monomer conversion and low polydispersities (PDI<1.15) up to high monomer to polymer conversion (>90%).     

Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 2. Exploring interactions at the proximal (S2) binding site

In an effort to increase the thrombin inhibitory activity of a novel series of inhibitors (i.e., 1a), substituents were incorporated at the C-3" position of the C-3 aryl ring (2). Consistent with the X-ray crystallography studies, small hydrophobic groups at the C-3" site (Br and Me) enhanced thrombin inhibitory activity by 8-fold. However, a few more hydrophilic substituents (NO2 and OMe) also enhanced the potency of the series. The biological results are discussed in terms of molecular modeling studies.     

Failure Analysis Case Study Information Disseminator

Since 1989, the American Society of Civil Engineers Technical Council on Forensic Engineering has conducted two surveys to gauge the need for teaching failure analysis topics in the civil engineering curriculum. Although the surveys addressed different topics, the limited availability of instructional materials in failure analysis was a recurring theme. The purpose of this paper is to respond to each of the questionnaires by reporting on the ongoing development of a preliminary Internet web site whereby consultants can contribute failure case studies. These case studies will then be readily available for professors and instructors to use in stand-alone failure analysis courses. The case studies can also be used as supplemental material and can be integrated into existing general civil engineering curriculum courses as well.     

High density lipoprotein (HDL), and not albumin, is the major palmitate binding protein in New Zealand long-finned (Anguilla dieffenbachii) and short-finned eel (Anguilla australis schmidtii) plasma

Plasma from two members of the teleost Anguillidae family, the New Zealand long-finned (Anguilla dieffenbachii) and short-finned eels (Anguilla australis schmidtii), were examined. Agarose gel electrophoresis showed both species had a major anionic diffuse protein band migrating at approximately the same position as human albumin, and autoradiography showed this protein bound [14C]palmitic acid, but not 63Ni2+. Cellulose acetate electrophoresis followed by Oil Red O staining suggested that this band was a lipoprotein. Two-dimensional electrophoresis of plasma showed the absence of a significant albumin band at approx. 65 kDa, and that the palmitate binding band appeared to be composed of at least three proteins, with the major protein running at 30 kDa. N-Terminal sequencing of the palmitate binding band indicated major sequences of DAPAPP(S)QLED- for long-finned eel and DAPAPPSQLEHV- for short-finned eel, confirming their identities as apo-AI, the major apolipoprotein of high density lipoprotein (HDL). When ultracentrifugation was used to separate the lipoproteins of each species, the anionic palmitate binding protein was found solely in the lipoprotein fractions. There was no evidence of albumin in plasma from either eel, and it appears that in its absence HDL takes on the role of fatty acid transport.     

Mechanisms underlying oocyte activation and postovulatory ageing

Mammalian oocytes undergo significant growth during oogenesis and experience extensive cytoplasmic and nuclear modifications immediately before ovulation in a process commonly referred to as oocyte maturation. These changes are intended to maximize the developmental success after fertilization. Entry of a spermatozoon into the oocyte, which occurs a few hours after ovulation, initiates long-lasting oscillations in the free intracellular calcium ([Ca(2+)](i)) that are responsible for all events of oocyte activation and the initiation of the developmental programme that often culminates in the birth of young. Nevertheless, the cellular and molecular changes that occur during maturation to optimize development are transient, and exhibit rapid deterioration. Moreover, fertilization of oocytes after an extended residence in the oviduct (or in culture) initiates a different developmental programme, one that is characterized by fragmentation, programmed cell death, and abnormal development. Inasmuch as [Ca(2+)](i) oscillations can trigger both developmental programmes in mammalian oocytes, this review addresses one of the mechanism(s) possibly used by spermatozoa to initiate these persistent [Ca(2+)](i) responses, and the cellular and molecular changes that may underlie the postovulatory cellular fragmentation of ageing mammalian oocytes.