title: Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.
abstract: Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.
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: D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001389:Azirines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D010003:Osteoarthritis / Q000188:drug therapy; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D001381:Azepines; D001389:Azirines; D004095:Dihydropyridines; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; C069267:diazipine; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2