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

Maria P. Giovannoni, Nicoletta Cesari, Alessia Graziano, Claudia Vergelli, Claudio Biancalani, Pierfrancesco Biagini, Vittorio Dal Piaz
2007 Journal of Enzyme Inhibition and Medicinal Chemistry  
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 (IC 50 ¼ 0.32 mM) for PDE4B (anti-inflammatory) than for PDE4D (IC 50 ¼ 2.5 mM), generally considered the subtype responsible for emesis. Moreover the ratio
more » ... ver 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 TNFa production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity.
doi:10.1080/14756360601114700 pmid:17674813 fatcat:rpa2bjms2zf3faatc4k4xtxiwi