Filippo Russo

High affinity and selectivity of [[(arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives for the 5-HT1A receptor. Synthesis and structure-affinity relationships

In this work we report the affinity of new thienopyrimidinones for 5-HT(1A)Rs and the selectivity versus alpha(1)ARs. The 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-6-ethyl -thieno[2,3-d]pyrimidin-4(3H)-one 27 is the most potent and selective (Ki 0.19 nM, selectivity 115). Compound 31 with the N4 piperazine orthonitrophenyl nucleus instead of the orthomethoxyphenyl also shows a good affinity and selectivity (Ki 1. 46 nM, selectivity 84). The results of derivatives 28, 29 and 30 (Ki 3.28, 12.59 and 4.38 nM; selectivity 24, 4 and 5, respectively), which have, respectively, an ethyl, an allyl and an acetylamino group instead of an N3 amino group, indicate the importance of this last group for the interaction with 5-HT(1A)R. Comparison of the results for the superior homologue 53 (Ki 3.72 nM, selectivity 51) and the inferior homologue 52 (5-HT(1A) Ki 1499 nM, alpha(1)A Ki NA) of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6,7-dimethyl-8H-[1, 3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidin-8-one 57 (Ki 23 nM, selectivity 5) shows how important the length of the chain binding the two heterocyclic systems is in the interaction with 5-HT(1A)Rs and alpha(1)ARs.

Synthesis of new thienopyrimidobenzothiazoles and thienopyrimidobenzoxazoles with analgesic and antiinflammatory properties

Abstract As an extension of research on analgesic and antiinflammatory compounds, a series of substituted analogues based on the novel 4H-thieno[2′,3′:4,5]pyrimido[2,1-b]benzothiazole and 4H-thieno[2′,3′:4,5]pyrimido[2,1-b]benzoxazole ring systems was synthesized. The compounds were obtained by reaction of 2-amino-3-carbethoxy-4,5-disubstituted thiophenes with 2-chlorobenzothiazole and 2-chlorobenzoxazole, respectively. Starting from 2-carbomethoxy-3-aminothiophene, 11H-thieno[3′,2′:4,5]pyrimido[2,1-b]-benzothiazol-11-one and 11H-thieno[3′,2′:4,5]pyrimido[2,1-b]benzoxazol-11-one were prepared in the same way. Synthesized compounds were evaluated for their potential analgesic activity in phenylquinone-induced writhing test in mice and for their potential antiinflammatory activity in carrageenan-induced rat-paw oedema test, in acetic-acid peritonitis assay and in croton oil-induced mouse-ear oedema test. 9,10,11,12-Tetrahydro-12H-benzothieno[2′,3′:4,5]pyrimido[2,1-b]benzoxazol-12-one 12 was the most active derivative in the series in all performed tests. It showed remarkable analgesic and antiinflammatory activities associated with an excellent gastric tolerance.

Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands.

This work reports the synthesis and the binding tests on the 5-HT3 and 5-HT4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT3 over the 5-HT4 receptor (5-HT3 Ki=3.92 nM, 5-HT4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester (41) showed the highest affinity and selectivity for the 5-HT4 over the 5-HT3 receptor (5-HT4 Ki=81.3 nM, 5-HT3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.

Pyrazolothiazolopyrimidine derivatives as a novel class of anti-inflammatory or antinociceptive agents: synthesis, structural characterization and pharmacological evaluation☆

Abstract As a part of a research program on anti-inflammatory-analgesic compounds, pyrazolothiazolopyrimidines 5a-f and 5g-i were prepared by cyclodehydration in 98% H 2 SO 4 or PPA of the corresponding 6-thioketomethylene-substituted-4-hydroxy-pyrazolo[3,4- d ]pyrimidines 2a-i and 2g-i . The results of the pharmacological in vivo screening indicate an interesting dissociation of the analgesic from the anti-inflammatory activity depending on aromatic or aliphatic substitution at the C4 of the thiazole ring. Analgesic activity was not associated with any narcotic effect; in addition, all the active compounds showed a remarkable systemic and gastric tolerance. This indicated a mode of action different from that of the classical nonsteroidal anti-inflammatory drugs, acting on prostaglandin biosynthesis. To clarify the mechanism or the mechanisms underlying the pharmacological activity of these and other closely related compounds, we initiated a ‘file chemical approach’ to various systems involved in the inflammatory process. At present, some of the more active in vivo compounds tested as substance P antagonists showed a moderate and possibly non-specific effect on NK 1 and NK 2 receptors.

[1,2,4]Triazole derivatives as 5-HT1A serotonin receptor ligands

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.

Synthesis and pharmacological properties of pyrazolotriazolopyrimidine derivatives

Abstract As a part of research on anti-inflammatory-analgesic compounds, pyrazolotriazolopyrimidines were prepared by cycling the corresponding 2-phenylamino-3-aminopyrazolo[3,4- d ]pyrimidin-4-one derivatives 3a–h with triethylorthoformate, in the presence of p -toluenesulfonic acid. The results of the pharmacological screening indicate that some of the derivatives which were tested, especially 3c and 6e , showed a good anti-inflammatory activity associated with non-narcotic analgesic properties and a remarkable systemic and gastric tolerance.

Synthesis and NK-2 antagonist effect of 1,6-diphenyl-pyrazolo [3,4-d]-thiazolo[3,2-a]4H-pyrimidin-4-one

Abstract 1,6-Diphenyl-pyrazolo[3,4-d]thiazolo[3,2-a]4H-pyrimidin-4-one caused parallel displacement of the dose-response curve to the NK-2 receptor agonist in the guinea pig trachea suggesting it acts as a competitive antagonist. It is not active in the NK-1 and NK-3 receptor binding assays. A Ca ++ channel blocking action at the voltage-operated channels (L-type) was observed.

Building a model of interaction at the NK-2 receptors: Polycondensed heterocycles containing the pyrimidoindole skeleton†

Summary The pyrazolopyrimidothiazole ring system (compound N, table II) has been previously reported by us as a new competitive antagonist (apparent pA 2 = 7.3 equiv to 55 nM) at NK2-receptors. As part of our investigation on polycondensed heterocycles containing the pyrimidine ring as antagonists of G-protein coupled receptors, pyrimidoindole derivatives were prepared and tested in order to probe the topography of the NK2-receptors and ascertain the pattern of frameworks that result in optimum affinity and specificity. The title indole derivatives 5, 11a-d, 12c, 13a,b and 14b were ‘de novo’ designed or selected from our chemical archives and prepared by up-to-date synthetic routes, thus exploring new synthetic methodologies. According to the established graphic computer model, none of the tested substances exhibited activity as a consequence of the violation of an excluded volume area due the unfavourable position of the aromatic substituents.

Pyrimido[5,4-b]benzofuran and pyrimido[5,4-b]benzothiophene derivatives Ligands for α1-and 5HT1A-receptors

Abstract A number of 3-phenylpiperazinylethyl pyrimido[5,4- b ]benzofuran-2,4-dione and pyrimido[5,4- b ]benzothiophene-2,4-dione derivatives 5–15 were designed as bioisosters of the previously reported pyrimido[5,4- b ]indole-2,4-diones and synthesized starting from the 3-amino-2-carboxybenzofuran and benzothiophene ethyl and methyl esters respectively. They were evaluated for their in vitro α 1 -adrenoceptor and 5HT 1A -receptor affinities by radioligand receptor binding assays. All target compounds showed good to excellent affinities for the α 1 -adrenoceptor with K i values in the subnanomolar range. Some compounds were also good ligands for the 5HT 1A -receptor with K i values in the nanomolar range. 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl]-1-methyl pyrimido[5,4- b ]benzothiophen-2,4-dione 15 was the most active derivative in displacing [ 3 H]-8-OH-DPAT from rat hippocampal membranes. There is evidence suggesting that the N 1 methyl group of the tricyclic moiety of the title compounds is probably able to undergo a Van der Waals interaction at the 5HT 1A -receptor binding site but not at the α 1 -adrenoceptor active site.

SYNTHESIS OF NEW THIAZINOINDOLE DERIVATIVES AND THEIR EVALUATION AS INHIBITORS OF HUMAN LEUKOCYTE ELASTASE AND OTHER RELATED SERINE PROTEASES

A novel thiazinoindole tricyclic ring system was designed as potential inhibitors of serine proteases. The compounds were synthesized by ring closure at 80–90°C in poliphosphoric acid of the appropriate N′-alkyl or aryl substituted indolylthiourea derivatives. Members of this class of compounds inhibited human leukocyte elastase (Ki=30–40 μM) and α-chymotrypsin.