Synthesis of pyrrolo[2,3-d]pyridazinones as potent,subtype selective PDE4 inhibitors |
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Authors: | Maria P Giovannoni Nicoletta Cesari Alessia Graziano Claudia Vergelli Claudio Biancalani Pierfrancesco Biagini |
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Institution: | Dipartimento di Scienze Farmaceutiche, Via U. Schiff 6, Sesto Fiorentino, 50019, Firenze, Italy |
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Abstract: | A series of pyrrolo2,3-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. |
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Keywords: | Pyrrolopyridazinones PDE4 subtypes inhibitors selectivity TNFα |
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