5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors

The structureeactivity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 \ubc 94.6 nM; KihA2A \ubc 1.11 nM; IC50hA2B \ubc 2214 nM; KihA3 \ubc 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki \ubc 1.44 nM; hA1/hA2A \ubc 216.0; hA3/hA2A \ubc 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR

Gaia Photometric Data: DR1 results and DR2 expectations

Gaia DR1 was released in September 2016 and contained a photometric catalogue of over 1 billion sources. At this stage, this only included mean G-band photometry and an estimate of the error. Even though this may sound limited in nature, interesting science can still be achieved with this data thanks to its quality. A high level overview of the photometric processing and some validation results will be presented. Additionally, epoch photometry in the G-band was released in Gaia DR1 for a small number of variable sources in the South Ecliptic Pole which covers the LMC. The second data release (Gaia DR2) is currently being prepared and, if available, some preliminary validation results will be presented. It is planned that this release will contain colour information in the form of integrated BP and RP photometry in addition to the latest G-band photometry

Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: Effect of the N-5 bond type on the affinity and selectivity at the four adenosine receptor subtypes

In the last few years, many efforts have been made to search for potent and selective human A3 adenosine antagonists. In particular, one of the most promising human A3 adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A3 adenosine receptors are the presence of a small substituent at the N8 position and an unsubstitued phenyl carbamoyl moiety at the N5 position. In this study, we report the role of the N5-bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structure-activity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach

Gaia Data Release 2 - Processing of the photometric data

Context. The second Gaia data release is based on 22 months of mission data with an average of 0.9 billion individual CCD observations per day. A data volume of this size and granularity requires a robust and reliable but still flexible system to achieve the demanding accuracy and precision constraints that Gaia is capable of delivering. Aims. We aim to describe the input data, the treatment of blue photometer/red photometer (BP/RP) low-resolution spectra required to produce the integrated GBP and GRP fluxes, the process used to establish the internal Gaia photometric system, and finally, the generation of the mean source photometry from the calibrated epoch data for Gaia DR2. Methods. The internal Gaia photometric system was initialised using an iterative process that is solely based on Gaia data. A set of calibrations was derived for the entire Gaia DR2 baseline and then used to produce the final mean source photometry. The photometric catalogue contains 2.5 billion sources comprised of three different grades depending on the availability of colour information and the procedure used to calibrate them: 1.5 billion gold, 144 million silver, and 0.9 billion bronze. These figures reflect the results of the photometric processing; the content of the data release will be different due to the validation and data quality filters applied during the catalogue preparation. The photometric processing pipeline, PhotPipe, implements all the processing and calibration workflows in terms of Map/Reduce jobs based on the Hadoop platform. This is the first example of a processing system for a large astrophysical survey project to make use of these technologies. Results. The improvements in the generation of the integrated G-band fluxes, in the attitude modelling, in the cross-matching, and and in the identification of spurious detections led to a much cleaner input stream for the photometric processing. This, combined with the improvements in the definition of the internal photometric system and calibration flow, produced high-quality photometry. Hadoop proved to be an excellent platform choice for the implementation of PhotPipe in terms of overall performance, scalability, downtime, and manpower required for operations and maintenance

Gaia Data Release 2 - Photometric content and validation

Aims. We describe the photometric content of the second data release of the Gaia project (Gaia DR2) and its validation along with the quality of the data. Methods. The validation was mainly carried out using an internal analysis of the photometry. External comparisons were also made, but were limited by the precision and systematics that may be present in the external catalogues used. Results. In addition to the photometric quality assessment, we present the best estimates of the three photometric passbands. Various colour-colour transformations are also derived to enable the users to convert between the Gaia and commonly used passbands. Conclusions. The internal analysis of the data shows that the photometric calibrations can reach a precision as low as 2 mmag on individual CCD measurements. Other tests show that systematic effects are present in the data at the 10 mmag level

Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and Structurally Simplified Analogs. Chemistry and SAR Profile as Adenosine Receptor Antagonists

A review.  Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors.  Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A1, A2A, A2B and A3.  In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes.  Both agonists and antagonists were used as pharmacol. tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compds. have reached clin. phases.  The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists.  A lot of synthetic work was made on this scaffold in order to obtain potent A2A and A3 antagonists.  Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions.  Nevertheless PTP derivs. are tricyclic compds. with a high mol. wt. which exhibit limitations such as poor aq. soly. and difficult synthetic prepn.  With the aim to obtain derivs. with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold.  Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivs., resp.  Synthetic strategies for these compds. were reported, combined with the SAR profile on the adenosine receptors

Simplification of Pyrazolo-triazolo-pyrimidine Nucleus for Searching New Adenosine Receptor Antagonists.

Blockade of adenosine receptors (ARs) lead to a broad variety of effects in several organ systems permitting to consider antagonists for ARs as potential therapeutic targets. Several classes of heterocyclic derivatives have been reported as ARs antagonists with high levels of both affinity and selectivity. [1] In particular, in the last years, the nucleus of pyrazolo-triazolo-pyrimidines as ARs antagonists was deeply investigated. Modulating the substitution at the N5, N7 and N8 positions potent and selective A2A (1) and A3 (2) ARs antagonists have been synthesized.[2,3] Nevertheless this class of compounds, such as other tricyclic structures, showed several problems such as poor water solubility and most importantly tangled synthetic preparation. On these bases we tried to simplify the nucleus in order to avoid the problems related to this structure. In particular we developed triazolo-triazines [4], triazolopyrimidines and the extremely basic arylstyrenes derivatives. All the obtained results will be summarized

Structural investigations on a novel class of 1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptor antagonists.

Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. In particular, in recent years we investigated in depth the nucleus of triazolo-pyrazolo-pyrimidine as a basis for designing ARs antagonists. Nevertheless, this class of compounds, like other tricyclic structures, was subject to poor water solubility and more importantly complicated synthetic routes. In consideration of these problems, medicinal chemists recently focused their attention on the synthesis of more simplified heterocyclic derivatives, in particular bicyclic systems. The 1,2,4-triazolo[1,5-c]pyrimidines possesses a low molecular weight and less nitrogen atoms than pyrazolo-triazolo-pyrimidines, thus it may be a scaffold with promising pharmacokinetics properties. A preliminary investigation on these molecules was carried out introducing arylacetyl or arylcarbamoyl moieties at the N5 position, which enhanced affinity at the hA2B and hA3 ARs, when utilized on the pyrazolo-triazolo-pyrimidine nucleus. In addition, in order to better investigate the possible substitutions on this scaffold, also moieties without a carbonyl group (alkyl and aryl moieties) were introduced at N5 position. Surprisingly, compound bearing the methylamino substitution at the 5 position displays high affinity (KihA3=4.14 nM) and selectivity (236, 25, 592-fold vs hA1, hA2A and hA2B ARs) at the hA3AR subtype . The analogue was docked in a homology model of the hA3AR based on the crystallographic structure of the hA2AAR, confirming the interactions with residues important to have potency at the hA3AR. References [1]Moro, S., et al. Med. Res. Rev. 2006, 26 (2), 131-159. [2]Cacciari, B., et al. Purinergic Signalling 2007, 3, 183-193