A series of pyrazoles and pyrazolo[3,4-d]pyridazinones were synthesized and evaluated for their PDE4 inhibitory activity. All the pyrazoles were found devoid of activity, whereas some of the novel pyrazolo[ 3,4-d]pyridazinones showed good activity as PDE4 inhibitors. The most potent compounds in this series showed an IC50 in the nanomolar range. The ability to inhibit TNF-a release in human PBMCs was determined for two representative compounds, finding values in the sub-micromolar range. SARs studies demonstrated that the best arranged groups around the heterocyclic core are 2-chloro-, 2-methyl- and 3- nitrophenyl at position 2, an ethyl ester at position 4 and a small alkyl group at position 6. Molecular modeling studies performed on a representative compound allowed to define its binding mode to the PDE4B isoform.

Functionalized pyrazoles and pyrazolo[3,4-d]pyridazinones: synthesis and evaluation of their phosphodiesterase 4 inhibitory activity / P.Biagini; C.Biancalani; A.Graziano; N.Cesari; M.Giovannoni; A.Cilibrizzi; V.Dal Piaz; C.Vergelli; L.Crocetti; M.Delcanale; E.Armani; A.Rizzi; P.Puccini; P.Gallo; D.Spinabelli; P.Caruso. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 1464-3391. - ELETTRONICO. - 18(2010), pp. 3506-3517.

Functionalized pyrazoles and pyrazolo[3,4-d]pyridazinones: synthesis and evaluation of their phosphodiesterase 4 inhibitory activity

GIOVANNONI, MARIA PAOLA;DAL PIAZ, VITTORIO;VERGELLI, CLAUDIA;CROCETTI, LETIZIA;
2010

Abstract

A series of pyrazoles and pyrazolo[3,4-d]pyridazinones were synthesized and evaluated for their PDE4 inhibitory activity. All the pyrazoles were found devoid of activity, whereas some of the novel pyrazolo[ 3,4-d]pyridazinones showed good activity as PDE4 inhibitors. The most potent compounds in this series showed an IC50 in the nanomolar range. The ability to inhibit TNF-a release in human PBMCs was determined for two representative compounds, finding values in the sub-micromolar range. SARs studies demonstrated that the best arranged groups around the heterocyclic core are 2-chloro-, 2-methyl- and 3- nitrophenyl at position 2, an ethyl ester at position 4 and a small alkyl group at position 6. Molecular modeling studies performed on a representative compound allowed to define its binding mode to the PDE4B isoform.
18
3506
3517
P.Biagini; C.Biancalani; A.Graziano; N.Cesari; M.Giovannoni; A.Cilibrizzi; V.Dal Piaz; C.Vergelli; L.Crocetti; M.Delcanale; E.Armani; A.Rizzi; P.Puccini; P.Gallo; D.Spinabelli; P.Caruso
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/393584
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