Kilovoltage energy imaging with a radiotherapy linac with a continuously variable energy range.

PURPOSE: In this paper, the effect on image quality of significantly reducing the primary electron energy of a radiotherapy accelerator is investigated using a novel waveguide test piece. The waveguide contains a novel variable coupling device (rotovane), allowing for a wide continuously variable energy range of between 1.4 and 9 MeV suitable for both imaging and therapy. METHOD: Imaging at linac accelerating potentials close to 1 MV was investigated experimentally and via Monte Carlo simulations. An imaging beam line was designed, and planar and cone beam computed tomography images were obtained to enable qualitative and quantitative comparisons with kilovoltage and megavoltage imaging systems. The imaging beam had an electron energy of 1.4 MeV, which was incident on a water cooled electron window consisting of stainless steel, a 5 mm carbon electron absorber and 2.5 mm aluminium filtration. Images were acquired with an amorphous silicon detector sensitive to diagnostic x-ray energies. RESULTS: The x-ray beam had an average energy of 220 keV and half value layer of 5.9 mm of copper. Cone beam CT images with the same contrast to noise ratio as a gantry mounted kilovoltage imaging system were obtained with doses as low as 2 cGy. This dose is equivalent to a single 6 MV portal image. While 12 times higher than a 100 kVp CBCT system (Elekta XVI), this dose is 140 times lower than a 6 MV cone beam imaging system and 6 times lower than previously published LowZ imaging beams operating at higher (4-5 MeV) energies. CONCLUSIONS: The novel coupling device provides for a wide range of electron energies that are suitable for kilovoltage quality imaging and therapy. The imaging system provides high contrast images from the therapy portal at low dose, approaching that of gantry mounted kilovoltage x-ray systems. Additionally, the system provides low dose imaging directly from the therapy portal, potentially allowing for target tracking during radiotherapy treatment. There is the scope with such a tuneable system for further energy reduction and subsequent improvement in image quality.

An end-to-end assessment on the accuracy of adaptive radiotherapy in an MR-linac.

PURPOSE: To develop and demonstrate an end-to-end assessment procedure for adaptive radiotherapy (ART) within an MR-guided system. METHODS AND MATERIALS: A 3D printed pelvic phantom was designed and constructed for use in this study. The phantom was put through the complete radiotherapy treatment chain, with planned internal changes made to model prostate translations and shape changes, allowing an investigation into three ART techniques commonly used. Absolute dosimetry measurements were made within the phantom using both gafchromic film and alanine. Comparisons between treatment planning system (TPS) calculations and measured dose values were made using the gamma evaluation with criteria of 3 mm/3% and 2 mm/2%. RESULTS: Gamma analysis evaluations for each type of treatment plan adaptation investigated showed a very high agreement with pass rates for each experiment ranging from 98.10% to 99.70% and 92.60% to 97.55%, for criteria of 3%/3 mm and 2%/2 mm respectively. These pass rates were consistent for both shape and position changes. Alanine measurements further supported the results, showing an average difference of 1.98% from the TPS. CONCLUSION: The end-to-end assessment procedure provided demanding challenges for treatment plan adaptations to demonstrate the capabilities and achieved high consistency in all findings.

Optical lens compression via transformation optics.

Transformation optics is widely associated with the design of unconventional electromagnetic devices, such as electromagnetic cloaks or concentrators. However, a wide range of conventional optical devices with potentially advantageous properties can be designed by the transformation optical approach. For example, a coordinate transformation can be introduced that compresses a region of space, resulting in an overall decrease in the thickness of an optical instrument such as a lens. The optical properties of a transformed lens, such as Fresnel reflection or aberration profile, are equivalent to those of the original lens, while the transformed lens and the bounding transformation optical material are thinner than the original lens. This approach to flattening the profile of a lens represents an advantage over the use of a higher dielectric material because it does not introduce greater Fresnel reflections or require a redesign of the basic optic. Though transformation optical media are generally anisotropic, with both electric and magnetic response, it is possible to arrive at a dielectric-only transformation optical distribution for a lens interacting with transverse-magnetic (TM) polarized light. The dielectric-only distribution can be implemented using broad-band, low-loss metamaterials. Lens designs for both a full transformation and a dielectric-only implementation are discussed and confirmed via finite-element simulations.

A Transient Radio Source near the Center of the Milky Way Galaxy.

In late December 1990, a new radio source appeared near the center of our galaxy rivaling the intensity of Sgr A(*) (the compact radio source at the galactic center). Following its first detection, the flux density of the galactic center transient (GCT) increased rapidly to a maximum 1 month later, and then declined gradually with a time scale of about 3 months. Surprisingly, the GCT maintained a steep radio spectrum during both its rising and decay phases. The neutral hydrogen (HI) absorption shows similar absorption to that in front of Sgr A(*); this indicates that the GCT lies near the galactic center. Furthermore, both HI and OH observations show an additional deep absorption at +20 kilometers per second with respect to the local standard of rest. Thus, the GCT is either embedded in or located behind a molecular cloud moving with that velocity. The cloud can be seen on infrared images. Its opacity is shown to be inadequate to conceal a supernova near the galactic center. It is argued that the GCT was probably transient radio emission from synchrotron-radiating plasma associated with an x-ray binary system.

Electron beam quality control using an amorphous silicon EPID.

An amorphous silicon EPID has been investigated to determine whether it is capable of quality control constancy measurements for linear accelerator electron beams. The EPID grayscale response was found to be extremely linear with dose over a wide dose range and, more specifically, for exposures of 95-100 MU. Small discrepancies of up to 0.8% in linearity were found at 6 MeV (8-15 MeV showed better agreement). The shape of the beam profile was found to be significantly altered by scatter in air over the approximately 60 cm gap between the end of the applicator and the EPID. Nevertheless, relative changes in EPID-measured profile flatness and symmetry were linearly related to changes in these parameters at 95 cm focus to surface distance (FSD) measured using a 2D diode array. Similar results were obtained at 90 degrees and 270 degrees gantry angles. Six months of daily images were acquired and analyzed to determine whether the device is suitable as a constancy checker. EPID output measurements agreed well with daily ion chamber measurements, with a 0.8% standard deviation in the difference between the two measurement sets. When compared to weekly parallel plate chamber measurements, this figure dropped to 0.5%. A Monte Carlo (MC) model of the EPID was created and demonstrated excellent agreement between MC-calculated profiles in water and the EPID at 95 and 157 cm FSD. Good agreement was also found with measured EPID profiles, demonstrating that the EPID provides an accurate measurement of electron profiles. The EPID was thus shown to be an effective method for performing electron beam daily constancy checks.

The Space Physics Environment Data Analysis System (SPEDAS).

With the advent of the Heliophysics/Geospace System Observatory (H/GSO), a complement of multi-spacecraft missions and ground-based observatories to study the space environment, data retrieval, analysis, and visualization of space physics data can be daunting. The Space Physics Environment Data Analysis System (SPEDAS), a grass-roots software development platform (www.spedas.org), is now officially supported by NASA Heliophysics as part of its data environment infrastructure. It serves more than a dozen space missions and ground observatories and can integrate the full complement of past and upcoming space physics missions with minimal resources, following clear, simple, and well-proven guidelines. Free, modular and configurable to the needs of individual missions, it works in both command-line (ideal for experienced users) and Graphical User Interface (GUI) mode (reducing the learning curve for first-time users). Both options have "crib-sheets," user-command sequences in ASCII format that can facilitate record-and-repeat actions, especially for complex operations and plotting. Crib-sheets enhance scientific interactions, as users can move rapidly and accurately from exchanges of technical information on data processing to efficient discussions regarding data interpretation and science. SPEDAS can readily query and ingest all International Solar Terrestrial Physics (ISTP)-compatible products from the Space Physics Data Facility (SPDF), enabling access to a vast collection of historic and current mission data. The planned incorporation of Heliophysics Application Programmer's Interface (HAPI) standards will facilitate data ingestion from distributed datasets that adhere to these standards. Although SPEDAS is currently Interactive Data Language (IDL)-based (and interfaces to Java-based tools such as Autoplot), efforts are under-way to expand it further to work with python (first as an interface tool and potentially even receiving an under-the-hood replacement). We review the SPEDAS development history, goals, and current implementation. We explain its "modes of use" with examples geared for users and outline its technical implementation and requirements with software developers in mind. We also describe SPEDAS personnel and software management, interfaces with other organizations, resources and support structure available to the community, and future development plans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11214-018-0576-4) contains supplementary material, which is available to authorized users.

Optical source transformations.

Transformation optics is a recently appreciated methodology for the design of complex media that control the propagation of electromagnetic and other types of waves. The transformation optical technique involves the use of coordinate transformations applied to some region of space, providing a conceptual means to redirect the flow of waves. Successfully designed devices to date have made use of transformations acting on passive space only; however, the technique can also be applied when source distributions (e.g., current and charge) are included within the space being transformed. In this paper we present examples of source transformations that illustrate the potential of these expanded transformation optical methods. In particular, using finite-element full-wave simulations, we confirm the restoration of dipole radiation patterns from both a distorted 'pin-wheel' antenna and a bent dipole partially occluded by a cylindrical scatterer. We propose the technique of source transformations as a powerful approach for antenna design, especially in relation to conformal antennas.

Transformation-optical design of adaptive beam bends and beam expanders.

We describe the design of adaptive beam bends and beam splitters with arbitrary bend and split angles by use of finite embedded coordinate transformations. The devices do not exhibit reflection at the entrance or exit surfaces. It is shown that moderate and practically achievable values of the relative permittivity and permeability can be obtained for beam bends and splitters with both small and large bend radius. The devices are also discussed in the context of reconfigurable metamaterials, in which the bend and split angles can be dynamically tuned. The performance of adaptive beam bends and splitters is demonstrated in full wave simulations based on a finite-element method. Furthermore, the design of an adaptively adjustable transformation-optical beam expander/compressor is presented. It is observed that a pure transformation-optical design cannot result in a reflectionless beam expander/compressor.

A low Z linac and flat panel imager: comparison with the conventional imaging approach.

Experimental and Monte Carlo simulations were conducted for an Elekta Ltd Precise Treatment System linac fitted with a low Z insert of sufficient thickness to remove all primary electrons. A variety of amorphous silicon based panels employing different scintillators were modelled to determine their response to a variety of x-ray spectra and produce an optimized portal imaging system. This study has shown that in a low Z configuration the vast majority of x-rays are produced in the nickel electron window, and with a combination of a carbon insert and caesium iodide based XVI-panel, significant improvement in the object contrast was achieved. For thin, head and neck-type geometries, contrast is 4.62 times greater for 1.6 cm bone in 5.8 cm water than the standard 6 MV/iViewGT system. For thicker, pelvis-type geometries contrast increases by a factor of 1.3 for 1.6 cm of bone in 25.8 cm water. To obtain images with the same signal-to-noise ratio as the 6 MV/iViewGT system, dose reductions of a factor of 15 and 4.2 are possible for 5.8 cm and 25.8 cm phantoms respectively. This design has the advantage of being easily implemented on a standard linac and provides a portal image directly from the therapy beam aperture.

Beam characterisation of the 1.5 T MRI-linac.

As a prerequisite for clinical treatments it was necessary to characterize the Elekta 1.5 T MRI-linac 7 MV FFF radiation beam. Following acceptance testing, beam characterization data were acquired with Semiflex 3D (PTW 31021), microDiamond (PTW 60019), and Farmer-type (PTW 30013 and IBA FC65-G) detectors in an Elekta 3D scanning water phantom and a PTW 1D water phantom. EBT3 Gafchromic film and ion chamber measurements in a buildup cap were also used. Special consideration was given to scan offsets, detector effective points of measurement and avoiding air gaps. Machine performance has been verified and the system satisfied the relevant beam requirements of IEC60976. Beam data were acquired for field sizes between 1 × 1 and 57 × 22 cm2. New techniques were developed to measure percentage depth dose (PDD) curves including the electron return effect at beam exit, which exhibits an electron-type practical range of 1.2 ± 0.1 cm. The Lorentz force acting on the secondary charged particles creates an asymmetry in the crossline profiles with an average shift of +0.24 cm. For a 10 × 10 cm2 beam, scatter from the cryostat contributes 1% of the dose at isocentre. This affects the relative output factors, scatter factors and beam profiles, both in-field and out-of-field. The average 20%-80% penumbral width measured for small fields with a microDiamond detector at 10 cm depth is 0.50 cm. MRI-linac penumbral widths are very similar to that of the Elekta Agility linac MLC, as is the near-surface dose PDD(0.2 cm) = 57%. The entrance surface dose is ∼36% of Dmax. Cryostat transmission is quantified for inclusion within the treatment planning system. As a result, the 1.5 T MRI-linac 7 MV FFF beam has been characterised for the first time and is suitable for clinical use. This was a key step towards the first clinical treatments with the MRI-linac, which were delivered at University Medical Center Utrecht in May 2017 (Raaymakers et al 2017 Phys. Med. Biol. 62 L41-50).

Reference dosimetry in magnetic fields: formalism and ionization chamber correction factors.

PURPOSE: Magnetic resonance imaging-guided radiotherapy (MRIgRT) provides superior soft-tissue contrast and real-time imaging compared with standard image-guided RT, which uses x-ray based imaging. Several groups are developing integrated MRIgRT machines. Reference dosimetry with these new machines requires accounting for the effects of the magnetic field on the response of the ionization chambers used for dose calibration. Here, the authors propose a formalism for reference dosimetry with integrated MRIgRT devices. The authors also examined the suitability of the TPR10 (20) and %dd(10)x beam quality specifiers in the presence of magnetic fields and calculated detector correction factors to account for the effects of the magnetic field for a range of detectors. METHODS: The authors used full-head and point-source Monte Carlo models of an MR-linac along with detailed detector models of an Exradin A19, an NE2571, and several PTW Farmer chambers to calculate magnetic field correction factors for six commercial ionization chambers in three chamber configurations. Calculations of ionization chamber response (performed with geant4) were validated with specialized Fano cavity tests. %dd(10)x values, TPR10 (20) values, and Spencer-Attix water-to-air restricted stopping power ratios were also calculated. The results were further validated against measurements made with a preclinical functioning MR-linac. RESULTS: The TPR10 (20) was found to be insensitive to the presence of the magnetic field, whereas the relative change in %dd(10)x was 2.4% when a transverse 1.5 T field was applied. The parameters chosen for the ionization chamber calculations passed the Fano cavity test to within ∼0.1%. Magnetic field correction factors varied in magnitude with detector orientation with the smallest corrections found when the chamber was parallel to the magnetic field. CONCLUSIONS: Reference dosimetry can be performed with integrated MRIgRT devices by using magnetic field correction factors, but care must be taken with the choice of beam quality specifier and chamber orientation. The uncertainties achievable under this formalism should be similar to those of conventional formalisms, although this must be further quantified.

Lethal and sub-lethal responses of the biogenic reef forming polychaete Sabellaria alveolata to aqueous chlorine and temperature.

Sabellaria alveolata, a reef-forming marine polychaete, was exposed to aqueous chlorine which is routinely used as an anti-fouling agent in power station cooling water. Worms were treated to a range of chlorination levels (0, 0.02, 0.1 and 0.5 mg l(-1) Total Residual Oxidant referred to as control, low, intermediate and high TRO) at mean and maximum summer temperatures (18 and 23 °C respectively). Overall mortality was relatively low, however a combination of high temperature and intermediate and high TRO resulted in a significant increase in mortality compared to the control and low TRO treatments. In contrast the extension of dwelling tubes was reduced at high TRO, but increased at low and intermediate TRO levels relative to the controls independent of temperature. Finally, tube strength was found to decrease with increasing TRO, again independent of temperature. On the basis of these findings, S. alveolata can be considered tolerant of one month exposures to low TRO at water temperatures up to and including the summer maxima for southern UK waters. However, at higher TRO levels and during warm weather, high mortality would be predicted.

2(1H)-quinolinones with cardiac stimulant activity. 3. Synthesis and biological properties of 6-imidazol-1-yl derivatives.

A series of 6-imidazol-1-yl-8-methyl-2(1H)-quinolinones was synthesized and evaluated for cardiac stimulant activity in dogs. The majority of compounds were prepared from an appropriate 6-imidazol-1-yl-2(1H)-quinolinone precursor or by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide. Introduction of a range of 5-substituents into 6-(2,4-dimethylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (1) reduced inotropic activity in anesthetized dogs (percentage increase in dP/dtmax) although replacement of the 2-methyl group by iodo (10) or cyano (11) substituents was well tolerated. The 2-methyl-4-chloro (15) and 2-methyl-4-(methylthio) (22) derivatives displayed similar potency to 1 (40-50% increase in dP/dtmax, 10-12.5 micrograms/kg) and these compounds were 3-5 times more potent than milrinone. Introduction of iodo (14), cyano (16), or acetyl (17) substituents into the 4-position approximately halved inotropic activity. In conscious dogs, 11 (0.25 mg/kg) and 16 and 17 (0.125 mg/kg) produced similar increases in cardiac contractility (decrease in the QA interval) to 1 (0.125 mg/kg) and maximum responses were maintained for at least 3 h. Dose-related (25, 125, 250 micrograms/kg) cardiac stimulant activity was demonstrated by 17 and after the higher doses a marked response (approximately 30% increase in dP/dtmax) was still observed after 7 h, in contrast to milrinone. The substantial increases in cardiac contractility observed with 16 and 17 in the conscious dog were not accompanied by any tachycardia. These compounds also displayed an overwhelming selectivity for increasing the force of cardiac contraction (greater than 120% increase in dP/dtmax) rather than heart rate (5-10 beats/min decrease) in the Starling heart-lung preparation. As a result of this beneficial pharmacological profile, 6-(4-acetyl-2-methylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (17, UK-66,838) was selected for preclinical development studies.

7-Heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin -2(1H)-one derivatives with cardiac stimulant activity.

A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin++ +-2 (1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity. Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo [2,1-b]quinazolin-2(1H)-one or by cyclization of an N-[(2-aminophenyl)methyl]glycinate with cyanogen bromide. Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP/dtmax) in anesthetized dogs. Potency could be further enhanced with a 9-methyl substituent (10-12). The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone. In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) was maintained for the whole 7-h test period. In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (greater than 150% increase in dP/dtmax) in the Starling heart-lung preparation. These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone.

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives.

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

New nonpeptide angiotensin II receptor antagonists. 3. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)pyridine derivatives.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 3-substituted 2,6-dialkylpyridine. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.005-0.5 microM. A variety of substituents was found to be effective at the 3-position of the pyridine ring. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-1.0 mg/kg. One of the compounds, 2-ethyl-5,6,7,8-tetrahydro-4-([2'-(1H-tetrazol-5-yl)biphenyl-4y l] methoxy)quinoline (26), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg po in AII-infused, conscious, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model compound 26 showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg po. Based on its profile, this compound, designated ICI D6888, has been selected for evaluation in volunteers.

2(1H)-quinolinones with cardiac stimulant activity. 2. Synthesis and biological activities of 6-(N-linked, five-membered heteroaryl) derivatives.

A series of 6-(N-linked, five-membered heteroaryl)-2(1H)-quinolinone derivatives was synthesized and evaluated for cardiotonic activity. Most compounds were prepared by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide or by condensation of a 2-amino-5-heteroarylbenzaldehyde or -acetophenone derivative with the ylide derived from triethyl phosphonoacetate. In anesthetized dogs, 6-imidazol-1-yl-8-methyl-2(1H)-quinolinone (3; 25 micrograms/kg) produced a greater increase in cardiac contractility (percentage increase in dP/dt max) than alternative 6-(five-membered heteroaryl)-substituted analogues (4-8). Introduction of 4-methyl (10) or 2,4-dimethyl (13) substituents into the imidazole ring of 3 produced a marked increase in inotropic activity, and these compounds were some 10 and 5 times more potent than milrinone. Most of these quinolinones also displayed positive inotropic effects (decrease in QA interval) in conscious dogs after oral administration (0.0625-1 mg/kg) and in many cases (3, 5-7, 9, 11, 13, 16) there was little difference in activities at both the 1- and 3-h time points. Compound 13 (62.5, 125, 250 micrograms/kg po) demonstrated dose-related cardiac stimulant activity which, in contrast to milrinone, was maintained over the whole 7-h test period. No changes in heart rate were detected at any dose level and compounds 3, 9, 10, and 13 also displayed high selectivity for the stimulation of cardiac contractile force rather than heart rate in the Starling dog heart-lung preparation. Increases in dP/dt max of approximately 50% were accompanied by heart rate changes of less than 10 beats/minute. Physicochemical measurements gave a log P of 1.64 for 13 with pKa values of 7.13 +/- 0.04 and 11.5 +/- 0.2 for the imidazole and quinolinone moieties, respectively. X-ray structural analysis of 13 showed the imidazole and quinolinone rings at 52 degrees to one another in close agreement with the minimum-energy conformation (30 degrees) suggested by PCILO calculations. 6-(2,4-Dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolinone (13, UK-61,260) is currently undergoing phase II clinical evaluation in congestive heart failure patients.

New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties, and structure-activity relationships of 2-alkyl benzimidazole derivatives.

On the basis of an extension of the literature lead 1, a series of benzimidazoles have been synthesized and shown to be angiotensin II (AII) receptor antagonists. The structure-activity relationships of these new antagonists have been explored and the key binding interactions defined. Molecular mechanics calculations were carried out on analogues of imidazole AII antagonists and conformationally restricted analogues were synthesized. The benzimidazole antagonists displaced AII in binding studies in vitro with IC50 values in the range 10(-5)-10(-7) M and antagonized the hypertensive effects of AII in vivo (rats) following intravenous administration with ED50 values in the range of 5-20 mg/kg.

2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives.

A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones (1) was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolysis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 micrograms/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers (2, 4-6), and potency was maintained with either mono- (13, 15) or di- (16) alkylpyridinyl substituents. Introduction of a 4- (24) or 7- (25) methyl group into 3 reduced inotropic activity, whereas the 8-isomer (26) proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27) were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 X 10(-7) to 5 X 10(-4) M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives.

A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.