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The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery stages for a better analog design. Herein in this work, to enable decision making on a project, we have synthesized by employing a Diversity-Oriented Synthetic (DOS) methodology, a small library of molecular fragments endowed with acidic properties. By combining in-silico and experimental methodologies these compounds were chemically characterized and, particularly, with the aim to know their physicochemical properties, the aqueous ionization constants (pKa), partition coefficients logD and logP of each fragment was firstly estimated by using molecular modeling studies and then validated by experimental determinations. A face to face comparison between data and the corresponding carboxylic acid might help medicinal chemists in finding the best replacement to be used. Finally, in the framework of Fragment Based Drug Design (FBDD) the small library of fragments obtained with our approach showed good versatility both in synthetic and physico-chemical properties., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rat brain guanosine binding sites were studied by (i). a pharmacological approach to confirm the hypothesis of the existence of specific G-coupled receptors for guanosine (1) and, for the first time, delineate a structure-activity relationship for a series of guanosine derivatives; (ii). a molecular modelling approach to design a pseudo-receptor construction. GTP and its non-hydrolysable analogue Gpp[NH]p decreased [3H]-guanosine binding to rat brain membranes. Gpp[NH]p 30 and 100 microM induced a dose-dependent decrease in [3H]-guanosine affinity and PTX pretreatment of rat brain membranes caused a 50% reduction in binding. In slices from rat brain cortex, guanosine induced a dose-dependent increase in intracellular cAMP. This increase is specific for guanosine, since neither the pretreatment with adenosine deaminase nor the A(1) and A(2) adenosine receptor antagonists were able to modify the guanosine-induced cAMP accumulation. The structure-activity relationship showed that the potency order of the best substances able to displace 50 nM [3H]-guanosine was guanosine (1)=6-thioguanosine (3)>8-bromoguanosine (4)>inosine (10)>7-methylguanosine (6)=3'-deoxyguanosine (9)>2'-deoxyguanosine (8)=guanine (11)=6-thioguanine (12)>>N(2)-methylguanosine (5). The competition studies confirmed that [3H]-guanosine site was distinct from the well characterized ATP and adenosine binding sites. The present results are rationalized in terms of a putative pseudo-receptor construct which includes all the relevant physicochemical interaction between guanosine analogues and their putative binding sites. This construct will be useful for the in silico screening of compound libraries in search for new potent and structurally diverse pharmacological tools.

The design and synthesis of 2-(3'-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGluR1 antagonist is reported. S-TBPG is characterized by the bioisosteric replacement of the distal carboxy group of 2-(3'-carboxybicyclo [1.1.1]pent-1-yl)glycine (S-CBPG) by a tetrazolyl moiety. Despite a moderate reduction in potency, S-TBPG is a selective mGluR1 antagonist (69 microM), with no activity at other mGluR subtypes. The interesting biological profile of S-TBPG, coupled with its peculiar chemical structure, is discussed in terms of the structure activity relationship (SAR) of mGluR1 antagonists.

In the present study an investigation of the structure-activity relationships in 9-ethylpurine derivatives, aimed at preparing A1, A2A, A2B, and A3 selective adenosine receptor antagonists, was undertaken. Our synthetic approach was to introduce various substituents (amino, alkoxy and alkynyl groups) into the 2-, 6-, or 8-positions of the purine ring. The starting compounds for each series of derivatives were respectively: 2-iodo-9-ethyladenine (9), obtained from 2-amino-6-chloropurine (5); 9-ethyl-6-iodo-9H-purine (11), 8-bromo-9-ethyl-adenine (3) and 8-bromo-9-ethyl-6-iodo-9H-purine (13), obtained from 9-ethyl-adenine (2). The synthesized compounds were tested in in vitro radioligand binding assays at A1, A2A, and A3 human adenosine receptor subtypes. Due to the lack of a suitable radioligand the affinity of the 9-ethyladenine derivatives at A2B adenosine receptors was determined in adenylyl cyclase experiments. In general, the series of 9-ethylpurine derivatives exhibited a similar pharmacological profile at A1 and A2A receptors whereas some differences were found for the A3 and the A2B subtypes. 8-Bromo-9-ethyladenine (3) showed higher affinity for all receptors in comparison to the parent compound 2, and the highest affinity in the series for the A2A and A2B subtypes (Ki = 0.052 and 0.84 microM, respectively). Analyzing the different substituents, a phenethoxy group in 2-position (10a) gave the highest A2A versus A2B selectivity (near 400-fold), whereas a phenethylamino group in 2- and 6-position (10b and 12b, respectively) improved the affinity at A2B receptors, compared to the parent compound 2. The presence of a hexynyl substituent in 8-position led to a compound with good affinity at the A3 receptor (4d, Ki = 0.62 microM), whereas (ar)alkynyl groups are detrimental for the potency at the A2B subtype. These differences give raise to the hope that further modifications will result in the development of currently unavailable leads with good affinity and selectivity for A2B adenosine receptors.

Among the recently reported 2-(ar)alkynyl derivatives of 5'-N-ethylcarboxamidoadenosine (NECA), the (R,S)-2-(3-hydroxy-3-phenyl-1-propyn-1-yl)NECA [(R,S)-PHPNECA or SCH 59761] was found to be a very potent agonist at A1 and A2A receptor subtypes, with a Ki of 2.5 nM and 0.9 nM, respectively. Furthermore, this compound showed an inhibitory activity on platelet aggregation 16-fold higher than NECA, being the most potent anti-aggregatory nucleoside reported so far. Since this compound bears a chiral carbon in the side chain, the diastereoisomer separation was undertaken both by chiral HPLC and by a stereospecific synthetic method. Binding assays have shown that the (S)-diastereomer is about fivefold more potent and selective than the (R)-diastereomer as agonist of the A2A receptor subtype [(S)-PHPNECA, KiA2A = 0.5 nM; (R)-PHPNECA, KiA2A = 2.6 nM]. Functional studies indicated that (S)-PHPNECA possesses marked vasodilating activity and produces a relevant decrease in heart rate. Moreover, the (S)-diastereomer proved to be about ten times more potent than the (R)-diastereomer in inducing cardiovascular effects, in in vivo hemodynamic studies. However, the greatest difference between these two enantiomers resulted in the platelet aggregation test: in fact, the (R)-diastereomer displayed an inhibitory activity similar to that of NECA, whereas the (S)-diastereomer was 37-fold more active than NECA as an inhibitor of rabbit platelet aggregation, induced by ADP. These data suggest that (S)-PHPNECA could be a useful tool to investigate the mode of binding of agonists to the platelet adenosine receptor subtype.