A series of pyrrolo[2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC50 = 0.32 μM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 μM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6. For compounds 8 and 15a the ability to inhibit TNFα production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity.

Synthesis of pyrrolo[2,3-d]pyridazinones as potent, subtype selective PDE4 inhibitors / M.GIOVANNONI; N.CESARI; A.GRAZIANO; C.VERGELLI; C.BIANCALANI; P.BIAGINI;V.DAL PIAZ. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - ELETTRONICO. - 22:(2007), pp. 309-318. [10.1080/14756360601114700]

Synthesis of pyrrolo[2,3-d]pyridazinones as potent, subtype selective PDE4 inhibitors

GIOVANNONI, MARIA PAOLA;VERGELLI, CLAUDIA;
2007

Abstract

A series of pyrrolo[2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC50 = 0.32 μM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 μM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6. For compounds 8 and 15a the ability to inhibit TNFα production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity.
2007
22
309
318
M.GIOVANNONI; N.CESARI; A.GRAZIANO; C.VERGELLI; C.BIANCALANI; P.BIAGINI;V.DAL PIAZ
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/316688
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