title: Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.
abstract: We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.
authors.affiliation: Department of Small Molecule Chemistry, Amgen Inc., Thousand Oaks, CA 91320-1799, USA.
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Shannon
authors.initials: S
authors.lastname: Rumfelt
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Roland
authors.initials: R
authors.lastname: Bürli
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kogan
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindstrom
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.forename: James
authors.initials: J
authors.lastname: Treanor
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D010726:Phosphodiesterase Inhibitors; D011619:Psychotropic Drugs; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases