Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors.
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
Wang
Yuguang
Y
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yuguang.wang@spcorp.com
Chackalamannil
Samuel
S
Hu
Zhiyong
Z
Boyle
Craig D
CD
Lankin
Claire M
CM
Xia
Yan
Y
Xu
Ruo
R
Asberom
Theodros
T
Pissarnitski
Dmitri
D
Stamford
Andrew W
AW
Greenlee
William J
WJ
Skell
Jeffrey
J
Kurowski
Stanley
S
Vemulapalli
Subbarao
S
Palamanda
Jairam
J
Chintala
Madhu
M
Wu
Ping
P
Myers
Joyce
J
Wang
Peng
P
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000478:Alkylation; D000818:Animals; D019540:Area Under Curve; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D015195:Drug Design; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D010413:Penis / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014970:Xanthines; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5