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.
Dipartimento di Scienze Farmaceutiche, Via U. Schiff 6, Sesto Fiorentino 50019, Firenze, Italy. mariapaola.giovannoni@unifi.it
Maria P
MP
Giovannoni
Nicoletta
N
Cesari
Alessia
A
Graziano
Claudia
C
Vergelli
Claudio
C
Biancalani
Pierfrancesco
P
Biagini
Vittorio
V
Dal Piaz
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