title: Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.
abstract: Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
authors.affiliation: Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA. simeongbowers@gmail.com
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Michael
authors.initials: M
authors.lastname: Ye
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Aubele
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sealy
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Wayman
authors.initials: W
authors.lastname: Chan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dappen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Yong L
authors.initials: YL
authors.lastname: Zhu
authors.forename: Paul
authors.initials: P
authors.lastname: Beroza
authors.forename: George
authors.initials: G
authors.lastname: Tonn
authors.forename: Heather
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoffman
authors.forename: Ruth
authors.initials: R
authors.lastname: Motter
authors.forename: Donald
authors.initials: D
authors.lastname: Fauss
authors.forename: Pearl
authors.initials: P
authors.lastname: Tanaka
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Jeanne
authors.initials: J
authors.lastname: Baker
authors.forename: Deepal
authors.initials: D
authors.lastname: Pandya
authors.forename: Linnea
authors.initials: L
authors.lastname: Diep
authors.forename: Kent
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: John P
authors.initials: JP
authors.lastname: Anderson
authors.forename: Marcelle
authors.initials: M
authors.lastname: Bergeron
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011621:Pteridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C496126:PLK2 protein, human