Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Boyle
Craig D
CD
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
Xu
Ruo
R
Asberom
Theodros
T
Chackalamannil
Samuel
S
Clader
John W
JW
Greenlee
William J
WJ
Guzik
Henry
H
Hu
Yuequing
Y
Hu
Zhiyong
Z
Lankin
Claire M
CM
Pissarnitski
Dmitri A
DA
Stamford
Andrew W
AW
Wang
Yuguang
Y
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; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D043264:Phosphodiesterase I / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat