title: Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
abstract: Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaei_huang@merck.com
authors.forename: Shaei
authors.initials: S
authors.lastname: Huang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Justin
authors.initials: J
authors.lastname: Steen
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
authors.forename: George
authors.initials: G
authors.lastname: Hartman
authors.forename: Steve
authors.initials: S
authors.lastname: Stirdivant
authors.forename: Bob
authors.initials: B
authors.lastname: Drakas
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Eileen
authors.initials: E
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: James
authors.initials: J
authors.lastname: Hardwick
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Marc
authors.initials: M
authors.lastname: Abrams
authors.forename: Steve
authors.initials: S
authors.lastname: Beck
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Rob
authors.initials: R
authors.lastname: Lobell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Mari
authors.initials: M
authors.lastname: Ikuta
authors.forename: Joan Zugay
authors.initials: JZ
authors.lastname: Murphy
authors.forename: Vinod
authors.initials: V
authors.lastname: Sardana
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Michael
authors.initials: M
authors.lastname: Reilly
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mahan
mesh_terms: D000818:Animals; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D015363:Quinolones; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1