title: Discovery of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-diones and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4.
abstract: The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
authors.affiliation: Chemical and Screening Sciences, and Oncology Research, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. tsouh@wyeth.com
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Liu
authors.forename: Gary
authors.initials: G
authors.lastname: Birnberg
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Mercy
authors.initials: M
authors.lastname: Otteng
authors.forename: Tritin
authors.initials: T
authors.lastname: Tran
authors.forename: Kristina
authors.initials: K
authors.lastname: Kutterer
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Tang
authors.forename: Ron
authors.initials: R
authors.lastname: Suayan
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Malini
authors.initials: M
authors.lastname: Ravi
authors.forename: Angela
authors.initials: A
authors.lastname: Bretz
authors.forename: Mary
authors.initials: M
authors.lastname: Grillo
authors.forename: John P
authors.initials: JP
authors.lastname: McGinnis
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour