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.
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.
Tsou
Hwei-Ru
HR
Chemical and Screening Sciences, and Oncology Research, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. tsouh@wyeth.com
Liu
Xiaoxiang
X
Birnberg
Gary
G
Kaplan
Joshua
J
Otteng
Mercy
M
Tran
Tritin
T
Kutterer
Kristina
K
Tang
Zhilian
Z
Suayan
Ron
R
Zask
Arie
A
Ravi
Malini
M
Bretz
Angela
A
Grillo
Mary
M
McGinnis
John P
JP
Rabindran
Sridhar K
SK
Ayral-Kaloustian
Semiramis
S
Mansour
Tarek S
TS