title: Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.
abstract: We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. marksplummer@gmail.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Plummer
authors.forename: Joseph
authors.initials: J
authors.lastname: Cornicelli
authors.forename: Howard
authors.initials: H
authors.lastname: Roark
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Skalitzky
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Stankovic
authors.forename: Susan
authors.initials: S
authors.lastname: Bove
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Annise
authors.initials: A
authors.lastname: Goodman
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.forename: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Xiao Kang
authors.initials: XK
authors.lastname: Lu
authors.forename: Brian
authors.initials: B
authors.lastname: Sanchez
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.forename: Ron
authors.initials: R
authors.lastname: Sarver
authors.forename: Timothy
authors.initials: T
authors.lastname: Braden
authors.forename: Richard
authors.initials: R
authors.lastname: Gowan
authors.forename: Xi Qiang
authors.initials: XQ
authors.lastname: Shen
authors.forename: Katherine
authors.initials: K
authors.lastname: Welch
authors.forename: Adam
authors.initials: A
authors.lastname: Ogden
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: Heidi
authors.initials: H
authors.lastname: Baum
authors.forename: Howard
authors.initials: H
authors.lastname: Miller
authors.forename: Craig
authors.initials: C
authors.lastname: Banotai
authors.forename: Cindy
authors.initials: C
authors.lastname: Spessard
authors.forename: Sandra
authors.initials: S
authors.lastname: Lightle
mesh_terms: D000818:Animals; D001389:Azirines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D010003:Osteoarthritis / Q000188:drug therapy; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D001389:Azirines; D004095:Dihydropyridines; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C069267:diazipine; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4