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Novel Pyrazolopyrimidopyridazinones with Potent and Selective Phosphodiesterase 5 (PDE5) Inhibitory Activity as Potential Agents for Treatment of Erectile Dysfunction

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Maria Paola Giovannoni,*^† Claudia Vergelli,^† Claudio Biancalani,^† Nicoletta Cesari,^† Alessia Graziano,^† Pierfrancesco Biagini,^† Jordi Gracia,^‡ Amadeu Gavaldà,^‡ and Vittorio Dal Piaz^†

Dipartimento di Scienze Farmaceutiche, Universit di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy, and Almirall Prodesfarma Research Center, Cardener 68-74, 08024 Barcelona, Spain

J. Med. Chem., 2006, 49 (17), pp 5363–5371

DOI: 10.1021/jm060265+

Publication Date (Web): August 2, 2006

To whom correspondence should be addressed. Phone and fax: +30-055-4573682. E-mail: mariapaola.giovannoni@unifi.it.

†

Università di Firenze.

‡

Almirall Prodesfarma Research Center.

Abstract

Pyrazolo[1‘,5‘:1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC₅₀ values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC₅₀ = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.

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Published In Issue August 24, 2006
Received March 9, 2006

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Article

Novel Pyrazolopyrimidopyridazinones with Potent and Selective Phosphodiesterase 5 (PDE5) Inhibitory Activity as Potential Agents for Treatment of Erectile Dysfunction

Abstract

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SciFinder Links

History

Recommend & Share

Related Content

Substituted Pyrazolopyridopyridazines as Orally Bioavailable Potent and Selective PDE5 Inhibitors: Potential Agents for Treatment of Erectile Dysfunction

The Next Generation of Phosphodiesterase Inhibitors: Structural Clues to Ligand and Substrate Selectivity of Phosphodiesterases

The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione Analogues

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