1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.
Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
Ukita
Tatsuzo
T
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, 532-8505, Osaka, Japan. t-ukita@tanabe.co.jp
Nakamura
Yoshinori
Y
Kubo
Akira
A
Yamamoto
Yasuo
Y
Moritani
Yasunori
Y
Saruta
Kunio
K
Higashijima
Takanori
T
Kotera
Jun
J
Fujishige
Kotomi
K
Takagi
Michino
M
Kikkawa
Kohei
K
Omori
Kenji
K
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005837:Genitalia, Male / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones
D007202:Indicators and Reagents; D007527:Isoenzymes; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5