Synthesis of pyrrolo[2,3-d]pyridazinones as potent, subtype selective PDE4 inhibitors.
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 microM) for PDE4B (anti-inflammatory) than for PDE4D (IC50 = 2.5 microM), 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 TNFalpha production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity.
Giovannoni
Maria P
MP
Dipartimento di Scienze Farmaceutiche, Via U. Schiff 6, Sesto Fiorentino 50019, Firenze, Italy. mariapaola.giovannoni@unifi.it
Cesari
Nicoletta
N
Graziano
Alessia
A
Vergelli
Claudia
C
Biancalani
Claudio
C
Biagini
Pierfrancesco
P
Dal Piaz
Vittorio
V
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000145:classification; D000818:Animals; D020134:Catalytic Domain; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011758:Pyrroles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human; D020889:Rolipram