title: Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.
abstract: 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.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
authors.forename: Craig D
authors.initials: CD
authors.lastname: Boyle
authors.forename: Ruo
authors.initials: R
authors.lastname: Xu
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Henry
authors.initials: H
authors.lastname: Guzik
authors.forename: Yuequing
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Claire M
authors.initials: CM
authors.lastname: Lankin
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skell
authors.forename: Stanley
authors.initials: S
authors.lastname: Kurowski
authors.forename: Subbarao
authors.initials: S
authors.lastname: Vemulapalli
authors.forename: Jairam
authors.initials: J
authors.lastname: Palamanda
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Joyce
authors.initials: J
authors.lastname: Myers
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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