title: Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors.
abstract: The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brnardic
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tasber
authors.forename: Justin T
authors.initials: JT
authors.lastname: Steen
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Dudkin
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.forename: Bob A
authors.initials: BA
authors.lastname: Drakas
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Eileen S
authors.initials: ES
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: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Beck
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Robert B
authors.initials: RB
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: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
mesh_terms: D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship