title: Novel potent pyrimido[4,5-c]quinoline inhibitors of protein kinase CK2: SAR and preliminary assessment of their analgesic and anti-viral properties.
abstract: We describe the discovery of novel potent substituted pyrimido[4,5-c]quinoline ATP-competitive inhibitors of protein kinase CK2. A binding model of the inhibitors with the protein was elaborated on the basis of SAR and revealed various modes of interaction with the hinge region. Representative analog 14k (CK2 IC(50)=9 nM) showed anti-viral activity at nanomolar concentrations against HIV-1. Orally available compound 7e (CK2 IC(50)=3 nM) reduced pain in the phase II of a murine formalin model. These preliminary data confirm that properly optimized CK2 inhibitors may be used for anti-viral and pain therapy.
authors.affiliation: Cylene Pharmaceuticals, San Diego, CA 92121, USA. fpierre@cylenepharma.com
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Pauline
authors.initials: P
authors.lastname: Bourbon
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: Eric
authors.initials: E
authors.lastname: Stefan
authors.forename: Levan
authors.initials: L
authors.lastname: Darjania
authors.forename: Ryan
authors.initials: R
authors.lastname: Stansfield
authors.forename: Caroline
authors.initials: C
authors.lastname: Ho
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; D047390:Casein Kinase II