Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu 5 ) hold great promise for the treatment of a variety of central nervous system disorders. We have recently reported that prop-2-ynylidenecycloalkylamine derivatives are potent and selective NAMs of the mGlu 5 receptor. In this work, we explored the amide, carbamate, sulfonamide, and urea derivatives of prop-2-ynylidenecycloalkylamine compounds with the aim of improving solubility and metabolic stability. In silico and experimental analyses were performed on the synthesized series of compounds to investigate structure-activity relationships. Compounds 12, 32, and 49 of the carbamate, urea, and amide classes, respectively, showed the most suitable cytochrome inhibition and metabolic stability profiles. Among them, compound 12 showed excellent selectivity, solubility, and stability profiles as well as suitable in vitro and in vivo pharmacokinetic properties. It was highly absorbed in rats and dogs and was active in anxiety, neuropathic pain, and lower urinary tract models.

Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4-Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5 / Graziani, Davide; Caligari, Silvia; Callegari, Elisa; De Toma, Carlo; Longhi, Matteo; Frigerio, Fabio; Dilernia, Roberto; Menegon, Sergio; Pinzi, Luca; Pirona, Lorenza; Tazzari, Valerio; Valsecchi, Anna Elisa; Vistoli, Giulio; Rastelli, Giulio; Ruga Riva, Carlo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 62:3(2019), pp. 1246-1273. [10.1021/acs.jmedchem.8b01226]

Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4-Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5

Pinzi, Luca
Membro del Collaboration Group
;
Rastelli, Giulio;RUGA RIVA, CARLO
2019

Abstract

Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu 5 ) hold great promise for the treatment of a variety of central nervous system disorders. We have recently reported that prop-2-ynylidenecycloalkylamine derivatives are potent and selective NAMs of the mGlu 5 receptor. In this work, we explored the amide, carbamate, sulfonamide, and urea derivatives of prop-2-ynylidenecycloalkylamine compounds with the aim of improving solubility and metabolic stability. In silico and experimental analyses were performed on the synthesized series of compounds to investigate structure-activity relationships. Compounds 12, 32, and 49 of the carbamate, urea, and amide classes, respectively, showed the most suitable cytochrome inhibition and metabolic stability profiles. Among them, compound 12 showed excellent selectivity, solubility, and stability profiles as well as suitable in vitro and in vivo pharmacokinetic properties. It was highly absorbed in rats and dogs and was active in anxiety, neuropathic pain, and lower urinary tract models.
28-gen-2019
62
3
1246
1273
Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4-Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5 / Graziani, Davide; Caligari, Silvia; Callegari, Elisa; De Toma, Carlo; Longhi, Matteo; Frigerio, Fabio; Dilernia, Roberto; Menegon, Sergio; Pinzi, Luca; Pirona, Lorenza; Tazzari, Valerio; Valsecchi, Anna Elisa; Vistoli, Giulio; Rastelli, Giulio; Ruga Riva, Carlo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 62:3(2019), pp. 1246-1273. [10.1021/acs.jmedchem.8b01226]
Graziani, Davide; Caligari, Silvia; Callegari, Elisa; De Toma, Carlo; Longhi, Matteo; Frigerio, Fabio; Dilernia, Roberto; Menegon, Sergio; Pinzi, Luca; Pirona, Lorenza; Tazzari, Valerio; Valsecchi, Anna Elisa; Vistoli, Giulio; Rastelli, Giulio; Ruga Riva, Carlo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1172748
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