N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of Potent and Selective Ligands at the Peripheral Benzodiazepine Receptor.

We report the synthesis and the affinity data at both the peripheral (PBR) and the central benzodiazepine receptors of a series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamide derivatives III, designed as conformationally constrained analogues of 2-phenylindole-3-acetamides II such as FGIN-1-27. Most of the new compounds showed a high specificity and affinity for PBR, with Ki in the nanomolar to subnanomolar range. The most potent ligands (4−7, 9, 13−27) stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classical ligands. The SARs of this new class of compounds are discussed

Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors,

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/ subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2- yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4- dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors

Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors,

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/ subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2- yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4- dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors

Synthesis and local anaesthetic activity of some 7-amino-2-dialkylaminoalkylpyrrolo [3,4-c] pyridine derivatives.

A number of 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c] pyridin-1,3(2H)-dione derivatives were synthesized and their local anaesthetic activity was evaluated in vivo by corneal anaesthesia in rabbits. Only compounds 3,9 and 14 showed any activity, albeit lower than that of the reference drug lidocaine

Synthesis of pyrrolo[3,4-c]pyridine derivatives possessing an acid group and their in vitro and in vivo evaluation as aldose reductase inhibitors

Derivatives of [pyrrolo[3,4-c]pyridin-1,3(2H)-dion-2-yl] alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested on rat lens enzyme. The acetic derivatives 2, 5 and 15a-d proved to be much more potent inhibitors than the propionic derivatives, 7 and 16a-d, and the iso-propionic derivatives, 3 and 6. The presence of a second planar aromatic area in the benzoyl derivatives 15a-d did not result in any increase in activity. Two of the most active compounds in vitro (2 and 5) were also evaluated in vivo as inhibitors of glutathione lens depletion in galactosemic rats. None of the compounds was found to be active in maintaining the rat lens glutathione level, suggesting possible problems of ocular bioavailability and metabolism. The aldose reductase inhibitory activity of compounds 2 and 15d was also discussed by taking into account their conformational and electronic characteristics evaluated by means of theoretical calculation

Benzisothiazole-1,1-dioxide alkanoic acid derivatives as inhibitors of rat lens aldose reductase

Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic lats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism

Acid derivatives of benzisothiazole-1,1-dioxide as inhibitors of rat lens aldose reductase

A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b, 11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally lower than that of the reference compound, Sorbinil. The presence of an acyl moiety on the amino group in position 6, as in the acetic and propionic derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in activity. A good potency was shown by compounds 14g and 15g, in which a second carboxylic function is present on the 6-acylamino group. Also the open products 16, which contain the phenylsulfonyl fragment found in several known inhibitors of aldose reductase, were obtained and tested in the rat lens assay

Geometrically Constrained Derivatives of Indolylglyoxylamides as Ligands Binding the GABAA/BzR Complex.

Indolylglyoxylamides are a class of distinctive benzodiazepine receptor ligands, proposed in the mid-eighties as open analogues of β-carbolines. Thorough and long-lasting studies of their structure-activity relationships led to the development of a great deal of derivatives, to satisfy increasingly structural and pharmacophoric requirements of the benzodiazepine binding site in the central nervous system. Efforts to pre-organize their flexible structure in the threedimensional shape adopted when bound to the receptor led to the identification of two novel classes of rigid ligands, characterized by planar tricyclic heteroaromatic cores: the [1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one and the [1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-dione. The present review focuses on these selected classes of ligands, whose rational development, in terms of chemical structures and structure-activity relationships, will be fully discussed

Geometrically Constrained Analogues N-Benzylindolylglyoxylylamides: [1,2,4]Triazino[4,3-a]benzimidazol-4(10H)-one Derivatives as Potential New Ligands at the Benzodiazepine Receptor.

A series of 3-benzylamino-and 3-arylalkylaminocarbonyl [1, 2, 4]triazino [4, 3-a]benzimidazoles 1—12 were synthesized and biologically assayed as geometrically constrained analogues of N-benzylindolylglyoxylylamides II, which are high affinity ligands at the benzodiazepine receptor (BzR). The intermediate 3-ethoxycarbonyl [1, 2, 4]triazino [4, 3-a]benzimidazol-4(10H)-one 14 and its N(10)-methyl analogue 15 closely related to 3-alkoxycarbonyl-β-carbolines I were also investigated. The title compounds exhibited a lower affinity compared with the corresponding indolylglyoxylylamide derivatives II. Attempts were made to rationalize these results taking into account the possible tautomeric equilibria involving these ligands