Optimization of Substituted N-3-Benzylimidazoquinazolinone Sulfonamides as Potent and Selective PDE5 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 43; no. 26; pp. 5037 - 5043
• Main Authors: Rotella, David P, Sun, Zhong, Zhu, Yeheng, Krupinski, John, Pongrac, Ronald, Seliger, Laurie, Normandin, Diane, Macor, John E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28-12-2000
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Biological and medical sciences; Cattle; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Drug Evaluation, Preclinical; Genital system. Reproduction; Humans; In Vitro Techniques; Male; Medical sciences; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Muscles; Penis - drug effects; Penis - physiology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacokinetics; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Rabbits; Rats; Structure-Activity Relationship; Nitrogen heterocycle; Isozyme; Lactam; Rabbit; Esterases; Corpus cavernosum; Selectivity; Phosphoric diester hydrolases; Pyrrolidine derivatives; Structure activity relation; Chlorine Organic compounds; Chemical synthesis; Dog; Fissipedia; Carnivora; Sulfonamide; Ether; Enzyme; Benzene derivatives; Oral administration; Enzyme inhibitor; Bioavailability; Lagomorpha; Tricyclic compound; In vitro; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Fluorine Organic compounds; Piperazine derivatives; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000336j

A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure−activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.