title: Pyridyl aminothiazoles as potent Chk1 inhibitors: optimization of cellular activity.
abstract: Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. vadim_dudkin@merck.com
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Dudkin
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.forename: Robert A
authors.initials: RA
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
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D000071877:Checkpoint Kinase 1; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human